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The Atomically Precise Gold/Captopril Nanocluster Au25(Capt)18 Gains Anticancer Activity by Inhibiting Mitochondrial Oxidative Phosphorylation

  • Sarita Roy Bhattacharya
    Sarita Roy Bhattacharya
    Department of Physical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
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  • Kaushik Bhattacharya
    Kaushik Bhattacharya
    Department of Molecular and Cellular Biology, University of Geneva, Sciences III, Geneva 1205, Switzerland
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  • Vanessa Joanne Xavier
    Vanessa Joanne Xavier
    Department of Molecular and Cellular Biology, University of Geneva, Sciences III, Geneva 1205, Switzerland
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  • Abolfazl Ziarati
    Abolfazl Ziarati
    Department of Physical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
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    Orcidhttps://orcid.org/0000-0001-6686-4758
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  • Didier Picard*
    Didier Picard
    Department of Molecular and Cellular Biology, University of Geneva, Sciences III, Geneva 1205, Switzerland
    *Email: [email protected]
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  • , and 
  • Thomas Bürgi*
    Thomas Bürgi
    Department of Physical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-0906-082X
Cite this: ACS Appl. Mater. Interfaces 2022, 14, 26, 29521–29536
Publication Date (Web):June 21, 2022
https://doi.org/10.1021/acsami.2c05054

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Atomically precise gold nanoclusters (AuNCs) are an emerging class of quantum-sized nanomaterials with well-defined molecular structures and unique biophysical properties, rendering them highly attractive for biological applications. We set out to study the impact of different ligand shells of atomically similar nanoclusters on cellular recognition and response. To understand the effects of atomically precise nanoclusters with identical composition on cells, we selected two different water-soluble gold nanoclusters protected with captopril (Capt) and glutathione (GSH): Au25(Capt)18 (CNC) and Au25(GSH)18 (GNC), respectively. We demonstrated that a change of the ligand of the cluster completely changes its biological functions. Whereas both nanoclusters are capable of internalization, only CNC exhibits remarkable cytotoxicity, more specifically on cancer cells. CNC shows enhanced cytotoxicity by inhibiting the OXPHOS of mitochondria, possibly by inhibiting the ATP synthase complex of the electron transport chain (ETC), and by initiating the leakage of electrons into the mitochondrial lumen. The resulting increase in both mitochondrial and total cellular ROS triggers cell death indicated by the appearance of cellular markers of apoptosis. Remarkably, this effect of nanoclusters is independent of any external light source excitation. Our findings point to the prevailing importance of the ligand shell for applications of atomically precise nanoclusters in biology and medicine.

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Introduction

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The field of nanotechnology has always intrigued researchers to find and develop novel nanomaterials for applications in our life. Nanoparticles have some disadvantages regarding the precise control of their size and the number of ligands on their surface. In contrast, ligand-protected metal nanoclusters are atomically precise and exhibit enhanced photoluminescence and other appealing properties for applications such as intrinsic chirality and magnetism. (1,2) Precise control of the size and structure provides a handle to tune the electronic properties of these nanoscale objects, which makes them attractive for applications in various domains like sensing, optics, enantio-separation, photocatalysis, and the biomedical field. (3−5)
The nontoxic nature of gold, the size-dependent fluorescence, and other molecule-like features make AuNCs appealing candidates for biomedical applications. (4) Furthermore, the ligand shell of AuNCs can easily be modified to impart proper functionality and recognition properties. For example, the detection of hydrogen sulfide (H2S) and sensing of l-dopamine in cerebrospinal fluid are the examples of the ligand shell modification. (6,7) The fluorescence of AuNCs ranges from near infra-red (NIR) over the visible range to ultraviolet (UV), and this can be achieved by tuning the size of nanoclusters to have a high quantum yield and large Stokes shift. (8) One of the early applications of water-soluble AuNCs in imaging relied on d-penicillamine-capped AuNCs. (9−11) The internalization of these clusters on Hela cells was studied by confocal microscopy with two-photon excitation for bio-imaging. (12)
Another emerging application field for nanoclusters is nanomedicine with the use of hydrophilic ligands. 6-Mercaptohexanoic acid (MHA)-protected AuNCs were successfully shown to impart antimicrobial activities toward gram-positive and gram-negative bacteria. (13) 6-MHA is also utilized for the synthesis of Au25(MHA)18 as a delivery vehicle for melittin. (14) In addition to the Au25(SR)18 nanocluster system, Au18(MPA)14 (MPA, mercaptopropionic acid) is also internalized by both gram-positive and gram-negative bacteria. The Au18(MPA)14 nanocluster by itself has some bactericidal effect, but a nanocomposite of Au18(MPA)14 with a photoporphyrin (PpIX) within a chitosan polymer matrix shows an enhanced bactericidal effect toward both gram-positive and gram-negative bacteria upon white light irradiation. (15) Similarly, in combination with photothermal and photodynamic therapy, AuNCs were shown to possess enhanced anticancer properties. AuNCs are promising candidates for photodynamic therapy due to singlet oxygen generation upon two-photon excitation. One can also increase the local bioavailability of singlet oxygen by embedding the nanocluster into hydrogel nanoparticles, thus enhancing the photoexcitation properties of AuNCs. (16)
Most of the earlier applications of water-soluble nanoclusters use intrinsic fluorescence properties of nanoclusters for bio-imaging or use the nanoclusters in combination with single-photon or two-photon excitation. In the latter applications, the cells were killed only upon laser exposure. In the field of monolayer-protected metal clusters, it has been shown that minor changes in the composition, such as the number of metal atoms and/or the change of ligand, can have a drastic effect on the properties of the sample (every atom count). It is likely that in a highly complex environment such as in cells, only minor changes of the nanoclusters can have drastic consequences. Therefore, it is essential to use atomically precise clusters rather than a mixture of different clusters in such studies because, in the latter case, only one cluster in the mixture may be responsible for an observed effect.
Not much attention was paid to the atomic precision of AuNCs when evaluating their interaction with cells. None of the reported studies revealed the influence of the ligand shell on the surface of atomically precise nanoclusters for cellular recognition and responses. Therefore, a thorough study of the impact of atomically precise nanoclusters on cells is warranted. Here, we explored the impacts of different capping ligands of an atomically precise Au25(SR)18 (-SR; thiolate ligand) nanocluster on cellular physiology and metabolism. We have selected and synthesized two well-defined water-soluble AuNCs, CNC and GNC, where the ligands are Capt and GSH, respectively. The choice of these two ligands is typically based on their nontoxicity to cells and their ability to give rise to identical atomically precise (Au25(-SR)18) AuNCs. (17,18) Additionally, it does not involve complicated synthesis methods for both AuNCs. Our study on the cell–nanocluster interactions reveals that the physiological impacts of an atomically precise nanocluster remarkably depend on the capping ligands. We discover that the formation of a type of nanocluster with a specific ligand leads to a completely different chemical entity with a ″gain of function″ property compared to the bare ligand by itself since, in comparison to Capt, CNC emerges as cancer-cell-specific cytotoxic agent.

Experimental Section

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Reagents and Resources

Details of all the reagents and resources are provided in Table S1 of the supplementary file.

Synthesis of Captopril (Capt) and Glutathione (GSH) Stabilized Nanoclusters

Synthesis of CNC and GNC was done according to previously reported methods. (19,20) For CNC synthesis, 0.2 mmol HAuCl4·3H2O (78.7 mg) was mixed with 0.23 mmol TOABr (126.8 mg) in 10 mL of methanol at room temperature for ∼25 min followed by the rapid addition of 1 mmol captopril (217.2 mg) in 5 mL of methanol. After ∼30 min, 2 mmol NaBH4 dissolved in ice-cold Milli Q water was injected rapidly at once. The reaction was continued for a minimum of 8 h until a reddish-brown solution was formed, indicative of Au25 nanocluster formation. Later, the solution was centrifuged to eliminate unreacted and insoluble gold-thiolate polymers. The supernatant collected was concentrated by rotatory evaporation followed by an ethanol precipitation step, and the pure CNC was extracted by dissolving the residue in a minimum volume of methanol. This purification step was repeated at least two more times to obtain pure CNC. Finally, the cluster was dried under a vacuum (Telstar Cryodo) to obtain a dry powder of pure CNC and stored at 4 °C for further experiments.
For GNC synthesis, in brief, an equal volume of 0.013 mmol HAuCl4·3H2O (5 mg) in Milli-Q water was mixed with a 0.052 mmol l-glutathione reduced (16 mg) solution in Milli-Q water. After the above mixture turned cloudy white, a solution of 0.132 mmol NaBH4 (5 mg) in 10 mL of ice-cold Milli-Q water was rapidly injected. Instantaneously, the color of the solution turned brown, indicative of Au25 nanocluster. The reaction mixture was kept in an oil bath at 60 °C for 2 h to complete the GNC synthesis. The solvent was then evaporated at low pressure and 50 °C by a rotatory evaporator to reduce the volume of the solution followed by the addition of methanol and centrifugation at high speed to precipitate the nanocluster. The reddish-brown precipitate of the nanocluster was dissolved in fresh Milli-Q water. The purification step was repeated once more to obtain the pure form of the GNC. The purified GNC solution was dried under a vacuum, and the nanocluster powder collected was preserved at 4 °C for further experiments.

Characterization of CNC and GNC

UV–vis absorption spectra were recorded on a Varian Cary 50 spectrophotometer using a quartz cuvette of 1 cm path length. All the spectra were recorded after dissolving the nanocluster solution in Milli-Q water. The spectra were normalized at 400 nm when required.
Mass spectra were recorded in positive mode using a Bruker Autoflex mass spectrometer equipped with a nitrogen laser. α-Cyano-4-hydroxycinnamic acid (α-CHCA) was used for CNC as the matrix with a 1:10, 1:100, and 1:1000 analyte/matrix ratio. α-CHCA (25 mM) was prepared in 50% acetonitrile/H2O with 0.1% trifluoroacetic acid. A volume of 2 μL of the analyte/matrix mixture was applied to the target and air-dried for the measurement. Electrospray high-resolution mass spectra (ESI HRMS) were measured on a QSTAR pulsar i (AB Sciex) using quadrupole and time-of-flight analyzers. The spectra were measured in the negative ion mode.
The fluorescence spectra were recorded at room temperature on a Fluorolog 3 (Horiba) spectrometer using a 10 × 2 mm quartz cuvette. The excitation wavelength was fixed at 514 nm (from a 450 W Xe lamp) in emission measurements. The emission was measured between 550 and 900 nm with identical excitation and emission slit widths of 5.0 nm.
Infrared spectra were measured on a Bruker Vertex 80V FTIR instrument. Briefly, the ligand (Capt/GSH) or cluster solution (CNC/GNC) was drop cast on CaF2 window and allowed to dry in air. IR spectra were recorded with a spectral resolution of 4 cm–1 in the range of 800–4000 cm–1.
A few drops of the samples (CNC and GNC) were placed on the carbon-coated copper grids (200 mesh), and the solvent was allowed to evaporate. The grids were then analyzed with a transmission electron microscope (TEM) at 120 or 160 kV (Tecnai G2, FEI, Eindhoven, Netherlands). Images were further analyzed with the ImageJ software to measure the diameter distribution and average values.
The hydrodynamic diameter and zeta potential of CNC and GNC were measured at room temperature using the dynamic light scattering (DLS) technique (Nano-ZS; Malvern Instruments, Malvern, United Kingdom). (20)

Cell Lines and Cell Culture

The following cells were used: HEK293T, human embryonic kidney cells; MDA-MB-231, triple-negative human breast carcinoma cells; HCT116, human colorectal carcinoma cells; A549, human lung epithelial carcinoma cells; HeLa, human cervical carcinoma cells; MCF7, estrogen receptor-positive human breast carcinoma cells; MAFs, mouse fibroblast derived from adult mouse ear tissue; HFs, human fibroblast cells derived from normal foreskin; HFs-hTERT, HFs immortalized by exogenous hTERT expression; HFs-hTERT + SV40 LT + Ras G12V, HFs-hTERT cells transformed into cancerous cells by overexpression of SV40 large T-antigen and mutant (G12V) H-Ras; (21) and RPE-1, retinal epithelial cells immortalized by hTERT expression. All these cells were maintained in Dulbecco’s modified Eagle medium (DMEM) supplemented with GlutaMAX, 10% fetal bovine serum (FBS), and penicillin/streptomycin (100 μg/mL) with 5% CO2 in a 37 °C humidified incubator. MCF10A (noncancerous epithelial) cells were grown in similar conditions in DMEM/F-12 supplemented with 5% heat-inactivated horse serum containing 10 ng/mL EGF, 5 μg/mL insulin, 1 μM dexamethasone, and penicillin/streptomycin (100 μg/mL).

Stability of Nanocluster in the Cell Culture Medium

CNC or GNC (300 μg/mL) was dissolved in pure Milli Q water or the cell culture medium, and UV–vis spectra were measured at different time (0–72 h) intervals.

Cell Viability Assay

The cell viability assay was performed by a CellTiter-Glo (CTG) luminescent assay (Promega) to directly quantify ATP generated by the cells, an indicator of metabolically active cells, as per the manufacturer’s instructions. Cells were seeded at a density of 10,000 cells/well (unless mentioned otherwise) at a volume of 100 μL/well in a complete medium in a 96-well plate, and after ∼12 h of seeding, the cells were treated with varied concentrations of CNC or GNC (0, 50, 100, 200, 300, 400, and 500 μg/mL) and their corresponding free ligands, i.e., Capt (0, 22.4, 44.4, 88.8, 133.2, 177.6, and 222 μg/mL) or GSH (0, 26.5, 53, 106, 159, 212, and 265 μg/mL) for 72 to 96 h (unless mentioned otherwise). Then 30 μL of the CellTiter-Glo reagent was added. After 15 min of incubation at room temperature (RT) in the dark, the luminescence was measured with a Cytation 3 (BioTek) cell imaging multimode microplate reader. The luminescence from the vehicle-treated cells was set to 100% viability. (22)

Flow Cytometry

For the flow-cytometric-based assay, a minimum of 10,000 cells was analyzed for each sample. We used FACS Gallios (Beckman Coulter) for acquiring the data, and the acquired data were analyzed with the FlowJo software package.

Measurement of Cell Death

Another way of measuring cytotoxicity is calculating the propidium iodide (PI) positive cells as membrane-altered dead cells by flow cytometry. For this, 4.0 × 105 cells/2 mL of medium in six-well plates were treated with CNC or GNC (0, 300, and 500 μg/mL) and their corresponding ligand: Capt (0, 133.2, and 222 μg/mL) or GSH (0, 159, and 265 μg/mL). After 72 h, cells were harvested by trypsinization, washed in phosphate-buffered saline (PBS), resuspended in 100 μL of PBS containing PI (2.5 μg/mL), and incubated for 15–20 min at 4 °C before flow cytometric acquisition was performed. (23)

Cell Cycle Analyses

Cells were harvested (as before) and fixed in 70% ice-cold ethanol, washed, incubated with 50 μg/mL PI for 15–20 min after treating with 100 μg/mL RNase A at RT for 5 min, and analyzed by flow cytometry. In some experiments, Hela cells (2 × 105) were pretreated with either a clathrin-mediated endocytosis (CME) inhibitor, Pitstop (40 μM), or a ROS scavenger, vitamin C (75 μM), for 1 h before the addition of CNC (0, 300, and 500 μg/mL), and the cell cycle assay was performed as described. Sub G0 cells (cells with nuclei containing less than a 2n DNA content) were used for the quantification of apoptotic cells. In experiments where G2/M phase arrests were measured, only diploid cell populations (nuclei containing 2n to 4n DNA content) were analyzed during data processing. (23)

Cell Counting by Trypan Blue Exclusion Assay

For this experiment, after treatments, viable cells were counted by trypan blue exclusion assay using a hemocytometer under the light microscope.

Scratch Assay

Highly invasive MDA-MB-231 cells were grown in complete DMEM as described before. After reaching 90% confluency, the cells were serum-starved for 24 h. Physical scratches were made with 10 μL pipette tips through the center of the wells, and cells were incubated with 222 μg/mL Capt and 500 μg/mL CNC. Images were captured by phase-contrast microscopy (described below) at different time intervals (0–24 h). (24)

Phase-Contrast Microscopy

Cellular morphology was analyzed using an inverted light microscope (Olympus CK2), and the images were captured with a Dino-lite camera using the DinoXcope software.

Confocal Microscopy

For confocal imaging experiments, HeLa or HEK293T cells (3 × 105) were seeded on a glass coverslip and transfected with plasmid pEGFP-C1 (for exogenous expression of intracellular enhanced green fluorescent protein (EGFP)). After ∼24 h post-transfection, cells were treated with CNC or GNC (500 μg/mL) and incubated for another 8 h in the incubator. Later, coverslips containing cells were washed with PBS and subsequently fixed with 4% formaldehyde for 20 min. After washing, the coverslips were mounted on a microscopic grade glass slide with Mowiol, and images were taken with Leica TCS SP5 confocal microscope with a 63× oil immersion objective. Cells labeled with a nanocluster (either CNC or GNC) were excited at 514 nm, and fluorescence was detected in the range of 640–788 nm. A sequential scanning setup was used to record the fluorescence from cells expressing EGFP proteins to avoid bleed-over of green fluorescence of EGFP into the red fluorescence (AuNC fluorescence region) channel. The excitation wavelength for measuring the fluorescence from EGFP was set at 488 nm, and the emission range at which fluorescence was measured was 501–540 nm. Digital images were acquired with 2.0–3.0× digital magnifications. Images were analyzed using the Image J-Fiji software. (25)
The study of endocytosis of CNC or GNC was carried out as described earlier. (26) HeLa cells were grown on coverslips for confocal imaging as described above at a low temperature (4 °C) in a complete medium containing 10 mM HEPES buffer for 1 h before the addition of CNC (300 μg/mL) and then incubated for another 8 h at 4 °C before slides were prepared for confocal imaging. The same set of experiments was performed at 37 °C, which served as a control.
For the endocytosis inhibition experiment by chemical inhibitors, slides were prepared for confocal imaging as described above. Briefly, HeLa cells were pretreated with Pitstop 2 (20 μM), Dynasore (80 μM), and cytochalasin D (5 μM) for 1 h, and subsequently, cells were treated with CNC (300 μg/mL) for an additional 8 h. Cells were processed as described above, and images were analyzed using the Image J-Fiji software. To quantitatively evaluate the uptake of nanoclusters into the cells, the imaging parameters were kept identical throughout the experiments. The relative amount of intracellular CNCs was estimated by measuring the intensity inside individual cells and is expressed as the mean fluorescence intensity calculated by selecting the area covered by cells in the collected images. This analysis was done using the Image J-Fiji software. A minimum of 50 cells was considered for calculating the mean fluorescence intensity. The software ImarisX64 9.5.1 was used for calculating Pearson’s correlation coefficient values.
For localization of CNC and GNC in mitochondria, we performed a confocal imaging assay. However, instead of the intracellular expression of EGFP, HeLa cells were transfected with mitochondrially targeted EGFP (mitoEGFP) and then treated with either CNC or GNC (300 μg/mL). (27) After 8 h of treatment, slides for confocal imaging were prepared, and data were analyzed with the Image J-Fiji software as described above.

Energy Metabolism Assays

The mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measurements were monitored with the Seahorse Bioscience Extracellular Flux Analyzer (XFe24, Seahorse Agilent) in real time, and cells were pretreated with the nanoclusters and ligands. (27,28) In brief, Hela cells (6 × 104) were cultured overnight in custom XF24 microplates in the DMEM GlutaMax medium. Before measurements, the cells were washed with unbuffered DMEM and incubated without CO2 for 1 h to acclimatize them to the assay medium.
For real-time treatment of nanoclusters (both CNC and GNC, 500 μg/mL) and corresponding ligands (222 μg/mL Capt and 265 μg/mL GSH), basal OCR and ECAR were determined for the first few minutes (∼20 min). Then CNC/GNC or ligands were added to record the mitochondrial stress test profile. After ∼90 min, sequential injections of oligomycin (5 μM), carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP; 1 μM), and a mixture of rotenone and antimycin (Rot: 1 μM, AA: 1 μM) were performed, and data were recorded for ∼24 min after each injection.
In pretreatment experiments, Hela cells were pretreated with nanoclusters, i.e., CNC/GNC (500 μg/mL), for different times (0–4 h) depending on the experiment, and 1 h before measurements, the cells were incubated in an unbuffered medium as described before. Following incubation in an unbuffered medium, the sequential addition of different inhibitors of mitochondrial ETC [(oligomycin, FCCP, and AA + Rot) or (AA + Rot, FCCP, and oligomycin)] was performed, and the metabolic profiles were measured as described above.
For HFs-hTERT cells and their transformed variant, 1 × 104 cells/well were seeded into XF24 cell culture microplates and processed as described above to compare their OCR profiles without any pretreatments with nanoclusters.

Measurements of Intracellular ROS

Cells (2 × 105) were treated with CNC/GNC (500 μg/mL), Capt (222 μg/mL), and GSH (265 μg/mL) for different time intervals (0–4 h), and the intracellular H2O2 (ROS) was assessed flow cytometrically by incubating with H2DCFDA (20 μM) for 30 min at 37 °C. For some experiments, HeLa cells (2 × 105) were pretreated with the inhibitors of CME (Pitstop 2, 40 μM and Dynasore, 80 μM) for 1 h before the treatment with CNC (500 μg/mL), and ROS was measured as described. (29)

Measurements of Mitochondrial ROS

Cells (2 × 105) were treated with CNC (500 μg/mL) for different times, and intramitochondrial ROS was measured by incubating the CNC/GNC- and ligands-treated cells with 5 μM Mitosox red for 15 min at 37 °C. Before acquiring the samples with a flow cytometer, stained cells were fixed with 4% formaldehyde. (29)

Mitochondrial Membrane Potential Assay

HeLa cells (2 × 105) were treated with CNC (500 μg/mL) at different time intervals (0–36 h), and after harvesting, the cells were incubated with MitoTracker Deep Red (500 nM) by incubating for 15 min at 37 °C, and the corresponding fluorescence was measured and analyzed by FACS. (29)

Immunoblot Assay

HeLa cells (1.5 × 106) were treated with CNC and GNC (0, 200, 300, 400, and 500 μg/mL) for 48 h. Proteins were extracted from the cells in the lysis buffer (20 mM Tris–HCl pH 7.4, 2 mM EDTA, 150 mM NaCl, 1.2% sodium deoxycholate, 1.2% TritonX-100, protease inhibitor cocktail (PIC)) and quantified by the Bradford method. An equivalent amount of proteins (75 μg) were resolved by 15% SDS-PAGE and transferred onto a nitrocellulose membrane (GVS Life Science) with a wet blot transfer system (VWR). The membranes were blocked with 2–5% nonfat milk in TBS-Tween 20 (0.2%) and incubated with primary antibodies (see Table S1 for reagent details) with the following dilutions: anti-Caspase 9 (1:1000) and anti-α-tubulin (1:5000). Lysates (50 μg) of HFs-hTERT cells and their transformed variant were resolved by 10% SDS-PAGE, processed as described above, and anti-H-Ras (1:1000) and anti-SV40 LT (1:750) antibodies were used to detect the corresponding proteins. Then membranes were washed with TBS-Tween 20 (0.2%) and incubated with the appropriate HRP-conjugated secondary antibodies (1:10,000 dilutions). Immunoblots were developed using the WesternBright chemiluminescent substrate (Advansta). Images were recorded with a LI-COR Odyssey image recorder.

RNA Extraction and Quantitative RT-PCR (qRT-PCR)

The TRIzol reagent (Thermo Fisher Scientific) was added directly to the cell monolayer for total RNA extraction, and RNA extraction was performed according to the manufacturer’s instructions. RNA (1 μg) from each sample was digested with RNase-free DNase (Promega), and the digested RNA was then reverse-transcribed to cDNA using random primers and the GoScript reverse transcription kit (Promega). qRT-PCR was performed using the GoTaq master mix kit (Promega) with CXF96 or Connect thermocyclers (BioRad). GAPDH was used as a reference gene for these experiments.

General Data Analyses

Data processing and analyses were performed using GraphPad Prism (version 8).

Results

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Characterization of Au25(Capt)18 and Au25(GSH)18 Nanoclusters

We selected two well-characterized AuNCs pairs, CNC and GNC, and their corresponding free ligands (Capt and GSH) to evaluate their biological effects on cellular functions (Figure 1a). The reported UV–vis absorption spectrum of Au25(SR)18 (R; Capt or GSH) has a prominent peak at 670 nm with two additional peaks at 450 and 400 nm, which is in agreement with previous findings and confirms the presence of CNC and GNC (Figure 1b). (19,20) The higher peak at 450 nm compared to the one at 400 nm in CNC and GNC confirms the anionic charge state for both nanoclusters. (19,20,30,31)

Figure 1

Figure 1. Characterization of CNC and GNC. (a) The top image shows the structure of the Au25(SR)18 nanocluster (color code: Au atoms, dark yellow; S atoms, green); the ligands (Capt or GSH) are omitted for clarity. The bottom image shows the structure of captopril (Capt) and glutathione (GSH) ligands used for the synthesis of CNC (Au25(Capt)18) and GNC (Au25(GSH)18). (b) UV–vis spectra of the synthesized CNC (red dotted line) and GNC (green squared line). The inset of the figure represents the color of the synthesized CNC and GNC in an aqueous solution. (c) The MALDI mass spectrum of CNC (Au25(Capt)18) recorded in positive mode with α-CHCA as the matrix. The peak marked with an asterisk (*) corresponds to the most important fragment Au21(Capt)14. (d) The ESI spectrum of GNC (Au25(GSH)18) gives characteristic peaks at m/z 809 and 1005 due to [Au(SG)2-H]−1 and [Au2(SG)2-H]−1, respectively. (e) The upper and lower panels, respectively, represent the morphology and size distributions of CNC and GNC obtained by TEM.

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We further confirmed the synthesis of CNC by performing matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) using α-CHCA as a matrix. We found the molecular ion peak for CNC (Figure 1c, left panel) to be at ∼8822 m/z (theoretical: ∼8818 m/z) with the predominant fragment at ∼7166 m/z (for Au21(Capt)14, theoretical: ∼7165 m/z) corresponding to a loss of ∼1656 m/z, i.e., Au4(Capt)4 unit (theoretical: ∼1653 m/z). The detailed analysis of the fragment peaks was described in the literature. (20) In ESI HRMS, since the spray is orthogonal to ion extraction in the instrument, only certain fragments such as [Au(SG)2-H]−1 (m/z) 808 (experimentally obtained value m/z, 809) and [Au2(SG)2-H]−1 (m/z) 1005 are detectable, which are in good agreement with the earlier reported value. (32) The spectra showed only the features due to the monolayers and smaller Au clusters in all the samples. Both CNC and GNC possess a well-characterized fluorescence emission peak in the range of 550–900 nm when excited at 514 nm wavelength (Figure S1a). We exploited these fluorescence properties of CNC/GNC to monitor their cellular uptake by confocal microscopy as described below.
The infrared spectra of Capt/CNC (Figure S1b, left panel) and GSH/GNC (Figure S1b, right panel) show the absence or reduction of the S–H stretching vibrational mode (2550–2600 cm–1) in CNC and GNC, which suggests the cleavage of S–H bond and binding of Capt or GSH molecules onto the surfaces of gold nanocluster (CNC/GNC) through Au–S bonding. From Figure S1b, it is also evident that the stretching mode ν(C═O) of free carboxylic acid group (∼1735 cm–1) of the ligand (Capt/GSH) is diminished or disappeared due to the formation of nanoclusters (CNC/GNC). (20)
The TEM images show well-dispersed spherical CNC (Figure 1e, upper panel) and GNC (Figure 1e, lower panel) with comparable average sizes (diameters) of 1.71 ± 0.02 and 1.6 ± 0.02 nm, respectively. The mean hydrodynamic sizes of the CNC and GNC were also measured by the dynamic light scattering technique (Figure S1c). The mean diameters of CNC (1.656 ± 0.26 nm) and GNC (2.116 ± 0.31 nm) are well within the range of previously reported values and agree with TEM analyses. (20,33) The average zeta potentials of CNC and GNC in the aqueous solution were 27.1 ± 3.23 and −33.1 ± 2.62, respectively.
Next, we monitored the stability of the nanoclusters in the cell culture medium by a UV–vis spectral analysis and found that both nanoclusters were stable even after incubation of 72 h (Figure S1d). The two major peaks at 670 and 450 nm, characteristic of Au25(SR)18 nanoclusters, remain unchanged, suggesting the structural integrity of the nanoclusters even in the nutrient-rich medium. However, a time-dependent increase in a peak at ∼550 nm was observed for CNC and GNC (Figure S1d). We speculate that the increase in the peak height at 550 nm could be indicative of the formation of a protein-nanocluster corona. The formation of such protein corona has been reported, and it is proposed that this phenomenon helps the cellular entry of nanoparticles. (4,34) We speculate that also nanoclusters are prone to form such protein corona.

Differential Cellular Response to Au25(Capt)18 and Au25(GSH)18 Nanoclusters

To evaluate the impacts of AuNCs on cellular viability, HEK293T cells were treated with various concentrations of CNC, GNC, and the corresponding free ligands. To our surprise, we observed that only CNC is cytotoxic to HEK293T cells (Figure 2a and Figure S2a). In contrast, GNC and the free ligands Capt and GSH are completely nontoxic within the used concentration range, as determined by cellular viability and morphological analyses (Figure 2a and Figure S2a).

Figure 2

Figure 2. Cytotoxicity of nanoclusters and ligands on cancer cells. (a) Effects of CNC and GNC (0–500 μg/mL) and the corresponding ligands (Capt and GSH, respectively) on cell viability measured by the CTG assay in HEK293T cells after 72 h treatment (n = 3 biologically independent samples). (b) Only CNC induces a higher percentage of cell death in HEK293T cells as determined by the PI staining assay measured by flow cytometry, whereas GNC and the corresponding ligands (Capt and GSH) are neutral (n = 4 biologically independent samples). Membrane ruptured cells can only be visualized by PI staining and designated as the ″dead cell″ population. (c) The left panel represents the apoptotic cell percentage calculated by the flow-cytometry-based cell cycle assay. Only CNC induces significant apoptosis. The right panel shows that CNC arrests HEK293T cells in the G2/M phase of the cell cycle (n = 3 biologically independent samples). For the bar graphs, the data are represented as mean values ± SEM (standard error of the mean).

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To further validate our results, we performed a flow-cytometry-based propidium iodide (PI) uptake assay to evaluate the cytotoxic effects of CNC. HEK293T cells treated with CNC showed PI-stained dead cells (Figure 2b). However, GNC, Capt, or GSH treatment showed only a marginal increase of dead cells compared to the control (Figure 2b). Next, we wanted to evaluate the impacts of CNC, GNC, and the free ligands on the cell cycle and apoptosis. HEK293T cells were treated with 300 and 500 μg/mL of CNC and GNC and the corresponding concentrations of the free ligands. As expected, only the CNC induced apoptosis as determined by the evaluation of the SubG0 (fragmented and <2n nucleus) cell population in the cell cycle analyses (Figure 2c, left panel). We also determined that CNC strikingly blocks the cell cycle progression of HEK293T cells in the G2/M phase (Figure 2c, right panel). However, GNC and the free ligands are totally nontoxic. These results were intriguing and showed that, specifically, CNC triggers apoptosis and a G2/M phase cell cycle arrest between two atomically precise identical AuNCs with different primarily nontoxic ligand shells.
All the above-mentioned cell-based cytotoxicity assays indicate a surprising and striking ″gain of function″ of CNC but not GNC. We speculate that when Capt ligands are clustered around an atomically precise gold core (Au25(SR)18 system), Capt changes its properties and becomes a new chemical species with additional functions. This phenomenon is ligand-dependent as the effect of GSH regarding cellular toxicity remains the same even in the form of a nanocluster.
To broaden the cytotoxicity spectrum of CNC, we performed cell viability assays and morphological assessments on different cancer cell lines upon treatment with CNC and Capt. CNC showed a dose-dependent inhibition of cell viability and cytotoxicity on MDA-MB-231 (triple-negative breast cancer), A549 (lung adenocarcinoma), HCT116 (colon carcinoma), and HeLa (cervical carcinoma) cells (Figure S2b,c).
The results shown above focus exclusively on cancer cells, and we wondered whether the cytotoxicity of CNC is limited to those. Therefore, we performed a similar cell viability assay on several noncancerous normal cell lines. Intriguingly, CNC is not as cytotoxic on normal cells as on cancer cells (Figure S2d). This result suggested that the cytotoxic ″gain of function″ of CNC is primarily specific to cancer cells.
We also checked the impact of CNC and its ligand on the migration of the highly invasive breast cancer cell line MDA-MB-231. CNC significantly reduces the migration of MDA-MB-231 cells into the scratched area, as evidenced by the scratch assay after 24 h of treatment (Figure S3). Free ligands behave like an inert component toward the cellular migratory property (Figure S3). Hence, CNC is not only cytotoxic but also inhibits cell migration and cell cycle progression.

Both CNC and GNC Internalize into Cells, and CNC Specifically Internalizes via Clathrin-Mediated Endocytosis (CME)

Next, we checked the intracellular uptake of these two AuNCs to understand the CNC-specific cytotoxicity. To study the intracellular uptake of CNC and GNC, Hela cells were treated with nanoclusters, and exploiting the red (pseudocolor) fluorescence (RF) properties of nanoclusters in confocal microscopy, comparative internalization was monitored qualitatively. (20,35) Colocalization of the RF and the green fluorescence (GF) from the exogenously expressed intracellular enhanced green fluorescence protein (EGFP; expressed from the pEGFP-C1 plasmid) served as an indicator of the internalization and intracellular localization of the nanoclusters. To confirm that the RF and the GF signals (specific to the nanocluster and EGFP, respectively) are only detected in the respective fluorescence channels, control sets with unstained cells, cells with only pEGFP-C1 transfection, and cells only treated with nanoclusters were analyzed (Figure 3a; first three rows of micrographs) and ruled out the possibility of ″bleed-over″ between the RF and GF signals. It must be noted that these transfection assays with pEGFP-C1 were transient transfections, and hence, it is expected that only a subset of the total cell population is transfected and ends up expressing EGFP.

Figure 3

Figure 3. Energy-dependent CME drives CNC internalization. (a) Dual-color confocal images of HeLa cells labeled with CNC (red color) and exogenously expressed intracellular EGFP (green color). The first row represents HeLa cells without transfection with the EGFP expression plasmid pEGFP-C1. The second and third rows represent cells stained with either CNC or cells transiently transfected with pEGFP-C1. The last row represents the transfected Hela cells with pEGFP-C1 and treated with CNC. The merging of the DIC (differential interference contrast) channel and the other two channels (red: CNC and green: EGFP channel) indicates the colocalization of CNC with EGFP as evident by the yellow color (n = at least 3 independent experiments). It must be noted that these transfection assays with pEGFP-C1 are transient transfections. Scale bar represents 10 μm. (b) The effect of temperature on CNC uptake by HeLa cells. Confocal microscopy of HeLa cells treated with CNC grown in two different temperatures: 4 and 37 °C (n = 2 independent biological samples). Scale bar represents 10 μm. (c) Bar graph representing the mean fluorescence intensity in arbitrary unit (a.u.) showing a comparison of CNC uptake at two different temperatures compared to control (n = a minimum of 50 cells was considered for calculating the mean fluorescence intensity, MFI). (d) Confocal images of HeLa cells pretreated with different endocytosis inhibitors and further incubated with CNC for 8 h to evaluate the uptake efficiency (n = 2 independent biological samples). Scale bar represents 10 μm. (e) Bar graph of mean fluorescence intensity (a.u.) relative to the control sample showing the effect of different inhibitors of the endocytic pathway on the uptake of CNC (n = a minimum of 50 cells was taken into account for calculating the MFI of a particular set). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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AuNC treatment on EGFP-expressing cells revealed the colocalization of these two fluorescence signals in a subset of cells as indicated by the yellow color in the merged images (Figure 3a and Figures S4 and S5). We calculated the Pearson’s correlation coefficients (PCC) to confirm the intracellular localization of nanoclusters by correlating the fluorescence derived from nanoclusters and intracellular EGFP. The PCC values for both CNC (0.269 ± 0.11) and GNC (0.343 ± 0.14) for Hela cells (Figure 3a and Figure S5, respectively), and CNC (0.628 ± 0.14) and GNC (0.728 ± 0.13) for HEK293T cells (Figure S4) indicated that, irrespective of the ligand, both the nanoclusters are equally capable of internalizing into the cells. Therefore, we ruled out the possibility that a differential ability of internalization into the cells is the primary reason for the differential cytotoxic behaviors of CNC and GNC.
To further explore how these nanoclusters might enter into cells, we decided to focus on the cytotoxic nanocluster, CNC. To determine whether the energy-dependent endocytosis mechanism drives the internalization of CNC into cells, HeLa cells were treated with CNC at a low temperature (4 °C). In agreement with the literature, (36,37) we also found reduced intracellular localization of CNC at 4 °C compared to the normal growth conditions (37 °C, Figure 3b,c). This result indicated that an energy-dependent endocytic mechanism is responsible for the internalization of CNC into cells.
One of the most well-studied mechanisms of internalizing foreign particles into cells is clathrin-mediated endocytosis (CME). To evaluate whether the intracellular uptake of CNC is CME-driven, (38,39) HeLa cells were pretreated with the known CME inhibitors Pitstop 2 and Dynasore before incubating with CNC. Both CME inhibitors markedly blocked the internalization of CNC into cells (Figure 3d,e). These findings were further confirmed by the treatment with cytochalasin D (CytoD, Figure 3d,e), which inhibits CME by blocking actin polymerization. (40) Together, these results confirmed that the internalization of CNC is CME-driven.

CNC Inhibits Mitochondrial OXPHOS

We further investigated the impact of these nanoclusters on the major cellular metabolic processes oxidative phosphorylation (OXPHOS) and glycolysis. OXPHOS coupled with the electron transport chain (ETC) and aerobic glycolysis are the sources of cellular energy production in the form of adenosine triphosphate (ATP). (41,42) The ETC is a series of large protein complexes (complex I, II, III, IV, and V) and is responsible for the sequential electron transfer from the most electropositive end (complex I) to the most electronegative end (molecular O2) via electron carriers including ubiquinone and cytochrome c. Complex V, the ATP synthase, generates ATP by utilizing the energy from the proton gradient generated across the mitochondrial inner membrane during the sequential electron transfer process. (43,44)
Impacts of nanoclusters on OXPHOS and glycolysis were monitored by measuring the oxygen consumption rates (OCRs) and the extracellular acidification rates (ECARs), respectively, with a Seahorse XF analyzer. (27,28,41,45) Real-time monitoring of the OCR after injection of the nanoclusters on the cells revealed that CNC, but not GNC, affects the OCR with a sudden increase followed by a gradual decrease over time (Figure 4a). The sudden increase in OCR after CNC injection was intriguing (Figure 4a). We speculate that this may be a cellular feedback mechanism to overcome the initial inhibition of OCR after exposure to CNC. To evaluate the activity profile of the ETC complexes, we sequentially injected oligomycin A (complex V/ATP synthase inhibitor), carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), and a mixture of antimycin A and rotenone (complex III and I inhibitors, respectively) on the cells. The addition of oligomycin A reduced the OCR as expected in the control and GNC treatment (Figure 4a). However, CNC-treated cells were unresponsive to oligomycin A, and the OCR followed the same slope as before (Figure 4a). These results indicated that CNC might be a complex V inhibitor, and since complex V is possibly inhibited in the CNC-treated cells, oligomycin A cannot further inhibit the same substrate. The subsequent addition of FCCP increased the OCR, a measure of the respiratory reserve capacity, in control and the GNC-treated sets as expected (Figure 4a). On the apparent contrary, the addition of FCCP did not positively impact the OCR of CNC-treated cells (Figure 4a), which seemed to have lost their respiratory reserve capacity. The subsequent addition of antimycin A and rotenone entirely killed the respiratory capacity in all the experimental sets (Figure 4a). These results suggested that although complex V is potentially blocked by CNC treatment, complexes I and III are still active and, therefore, can be inhibited by their respective inhibitors.

Figure 4

Figure 4. CNC inhibits complex V of mitochondrial ETC. (a) OCR and (b) ECAR of HeLa cells were monitored using the Seahorse Bioscience Extra Cellular Flux Analyzer in real time. The first few minutes (∼20 min) represent the basal OCR or ECAR of HeLa cells followed by the injection of nanoclusters and then the sequential addition of the ATP synthase inhibitor (oligomycin 5 μM), FCCP (1 μM), and a mixture of rotenone (1 μM) and antimycin (1 μM) was performed. OCR is an indicator of mitochondrial respiration, and ECAR is predominately a measure of glycolytic flux. (c) OCR and (d) ECAR of HeLa cells pretreated with either CNC or GNC for different times (1, 2, and 4 h) and effect of mitochondrial inhibitors in the same order (oligomycin, FCCP, and rotenone + antimycin). (e) OCR and (f) ECAR of Hela cells pretreated with either CNC or GNC for different times (1, 2, and 4 h). Note that the order of addition of the inhibitors was changed. Here, pretreated cells were first treated with the antimycin A and rotenone mixture and subsequently with FCCP and oligomycin A. All data are reported as means ± SD (n = 3 experimental sets). (g) ATP production rates are calculated from the data presented in panel c for HeLa cells pretreated with CNC and GNC. The ATP production rate is calculated as (last OCR measurement before oligomycin injection) – (OCR rate measured after oligomycin injection). All data are presented as means ± SEM (n = minimum of 3 independent biological samples). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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Any inhibition of the OCR can induce the glycolytic flux, which can be monitored by the ECAR. (46) We found that the inhibition of the OCR by the CNC treatment is complemented by an enhanced glycolytic flux (Figure 4b). To exclude the possibility that the addition of CNC can lower the pH of the solution by itself, the pH of the unbuffered medium was measured before and after the addition of CNC and GNC. None of these two nanoclusters affect the pH of the medium (data not shown). Therefore, the CNC-induced enhancement of ECAR is due to the inhibition of the OCR rather than the direct influence of the nanoclusters on pH. Additionally, in the identical experimental setups, the free ligands did not significantly impact the OCR and ECAR (Figure S6).
Metabolic flux measurements with CNC- and GNC-pretreated HeLa cells were performed to validate these findings further. Reminiscent of the real-time metabolic flux assays, we found that only the CNC-pretreated cells were nonresponsive to oligomycin A, which further confirmed the inhibition of complex V upon CNC treatment (Figure 4c). The enhanced basal ECAR of CNC-pretreated cells also supported the inhibition of OXPHOS (Figure 4d, first 20 min). Additionally, as expected, CNC-pretreated cells totally lost their respiratory reserve capacity (Figure 4c).
To find the impact of CNC on the activities of complexes I and III, CNC- and GNC-pretreated cells were first injected with the mixture of antimycin A and rotenone and, subsequently, with FCCP and oligomycin A. Irrespective of the pretreatment, the mixture of antimycin A and rotenone almost completely killed the OCR in all the experimental sets (Figure 4e). Interestingly, unlike CNC-pretreated cells, the mixture of antimycin A and rotenone augmented the ECAR of control and GNC-pretreated cells (Figure 4f). This result further confirmed that although complexes I and III remain active after the CNC pretreatment, glycolytic flux is already saturated due to the CNC-mediated inhibition of complex V.
The inhibition of complex V should reduce the production of ATP linked with mitochondria. Therefore, the rate of mitochondria-linked ATP production was measured. (27) As expected, only CNC but not GNC blocks the mitochondria-linked ATP production (Figure 4g). Together, these results demonstrated the following: (1) CNC blocks mitochondrial respiration, (2) CNC may be a novel inhibitor of mitochondrial ATP synthase (complex V), and (3) the ″gain of function″ of CNC compared to free captopril is due to a novel ″mito-poison″ activity. (29,47)

CNC Induces the Generation of Both Total Cellular and Mitochondrial ROS

Specific blockage in the ETC can initiate premature leakage of electrons from the mitochondrial respiratory complexes to the mitochondrial lumen, which induces the partial reduction of molecular oxygen to superoxide radical and further conversion into hydrogen peroxide. Hence, mitochondrial and overall intracellular ROS levels are augmented. (48,49) Since CNC inhibits complex V, we hypothesize that it should also increase intracellular ROS levels. The total intracellular ROS levels in HeLa cells were measured by 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) staining upon treatment with both nanoclusters and their corresponding free ligands. In agreement with our metabolic efficiency analyses (Figure 4a–g), we found that only CNC induces the generation of ROS, supporting the idea of the ″gain of function″ upon nanocluster formation with Capt (Figure 5a). The augmentation of CNC-driven mitochondrial ROS was measured with MitoSox Red, a mitochondrial superoxide reactive dye (Figure 5b). Moreover, this augmentation of mitochondrial ROS was perfectly correlated with the depolarization of the mitochondrial membrane potential upon CNC treatment as determined by the staining of MitoTracker Deep Red, a mitochondrial-membrane-potential-dependent dye (Figure 5c).

Figure 5

Figure 5. CNC-induced mitochondrial respiratory dysfunction triggers intracellular ROS and apoptosis. (a) Intracellular ROS levels were measured by flow cytometry using the H2DCFDA staining assay in HeLa cells treated with CNC, GNC, and their corresponding ligands. For the line graphs, the data are represented as mean values ± SEM (n = 4 biologically independent samples). (b) Mitochondrial ROS levels were measured in HeLa cells after treatment with CNC (500 μg/mL) using MitoSox staining (n = 4 biologically independent samples). (c) Bar graph representing the percentage of mitochondrial membrane depolarized cells as a function of time (0, 3, 6, 12, 24, and 36 h) upon CNC (500 μg/mL) treatment (n = 4 biologically independent samples). (d) Confocal images of HeLa cells transiently transfected with mitochondrially targeted EGFP (mitoEGFP) and later treated with CNC to study the colocalization of CNC into mitochondria. The first row represents HeLa cells without transfection with mitoEGFP. The second and third rows represent cells either stained with CNC or transiently transfected with mitoEGFP. The last row represents HeLa cells transiently transfected with mitoEGFP and then treated with CNC to study the colocalization of CNC into mitochondria. The yellow color in the merged image confirms the localization of CNC in mitochondria. It has to be noted that these transfection assays with pEGFP-C1 are transient transfections. (e) Western blot analysis of Hela cells after treating them with different concentrations of CNC and GNC (200, 300, 400, and 500 μg/mL). The analysis indicates that CNC strikingly reduces the pro-form of caspase 9. α-Tubulin served as a loading control.

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Both Nanoclusters Localize in Mitochondria, but Only CNC Triggers Caspase-Induced Apoptosis

Since CNC treatment leads to the inhibition of complex V, we speculated that CNC might also localize into mitochondria. To test this hypothesis, we expressed a mitochondrially targeted EGFP (mitoEGFP) in HeLa cells (27) and evaluated the colocalization of nanoclusters and mitoEGFP by confocal microscopy. Nevertheless, we confirmed no ″bleed-over″ between RF and GF signals derived from CNC/GNC and mitoEGFP, respectively (Figure 5d and Figure S7).
The dual-color confocal microscopy confirmed the localization of both CNC (Figure 5d, bottom row, and Figure S7a) and GNC in mitochondria (Figure S7b). It is important to note that due to the toxic nature of CNC, we reduced the incubation time with the nanoclusters to only 8 h for these colocalization studies. That might explain why there are relatively few and only weakly stained CNC- or GNC-positive cells in these confocal microscopy images. Additionally, the reduced fluorescence of nanoclusters in some cells may also be explained by the phenomenon of quenching of fluorescence of metal nanoclusters in the presence of various cellular substances. (6,50,51)
An increase in ROS leads to apoptosis via DNA damage, lipid peroxidation, mitochondrial dysfunction, and protein structure/function alterations. (52,53) Since CNC is cytotoxic and is also shown to inhibit the mitochondrial ETC, perhaps through complex V, we decided to examine the molecular signatures of apoptosis in CNC-treated cells.
We checked one of the major caspase proteins, caspase 9, associated with mitochondrial-dysfunction-mediated apoptosis. (54) We found that the expression level of pro-caspase 9 is strikingly reduced only in CNC treatment (Figure 5e). The downregulation of the pro-form of caspases in the process of cell death is a direct measure of their cleavage and formation of the enzymatically active form. (55) This result suggested that the mitochondrial-dysfunction-mediated induction of caspase 9 conceivably induces the caspase cascade activation only in the CNC treatment. Note that, although we observed the downregulation or reduction of the levels of pro-caspase tested here, we did not observe any strong signal for the activated caspase form. Since we performed this experiment after 48 h of treatment, we speculate that the labile nature of the active forms of caspases is the potential reason behind this observation. (56) Together, we concluded that CME-mediated internalized CNC localizes to mitochondria, potentially inhibits complex V of the mitochondrial ETC, triggers ROS generation, and subsequently initiates the mitochondria-mediated apoptotic response.

Inhibition of Internalization of CNC Protects Cells from Death

To test the hypothesis that impairing the internalization of CNC might result in reduced ROS generation, HeLa cells were pretreated with CME inhibitors and subsequently treated with CNC to check the total ROS generation by H2DCFDA staining. Both CME inhibitors, Pitstop 2 and Dynasore, reduce the CNC-induced ROS generation in HeLa cells (Figure 6a).

Figure 6

Figure 6. Restriction in the internalization of CNC protects cells from cell cycle arrest and reduced viability. (a) A comparison of intracellular ROS levels measured in Hela cells treated with CNC (500 μg/mL, red line) and HeLa cells pretreated with endocytic inhibitors Pitstop 2 (40 μM, blue line) and Dynasore (80 μM) to block the uptake of CNC inside the cells. (b) Cell cycle analysis revealed that pretreatment of Pitstop 2 (40 μM) on Hela cells partially protects from CNC (500 μg/mL)-induced G2/M phase cell cycle arrest. (c) A significantly higher number of viable cells were found in the case of HeLa cells pretreated with Pitstop 2 (40 μM) followed by CNC treatment compared to cells treated with only CNC. (d) Cell cycle analysis revealed that vitamin C (75 μM) pretreatment on Hela cells partially protects them from CNC-induced G2/M phase cell cycle arrest. (e) A significantly higher number of viable cells were found in the case of HeLa cells pretreated with vitamin C (75 μM) followed by CNC treatment compared to cells treated with only CNC. The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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Since CME inhibitors reduce the CNC-mediated ROS generation, we hypothesized that they might also protect cells from CNC-induced death. Hence, HeLa cells were treated with the CME-inhibitor Pitstop 2 and CNC, alone and in combination. Remarkably, Pitstop 2 inhibits the cytotoxic effect of CNC, as demonstrated by a reduced G2/M phase cell cycle arrest and by a relatively higher number of viable cells (Figure 6b,c). Additionally, vitamin C was used as a ROS-scavenging agent to check whether CNC-induced ROS promotes cytotoxicity. Remarkably, vitamin C significantly protects cells from CNC-mediated cytotoxicity (Figure 6d,e). Therefore, intracellular uptake and subsequent enhanced ROS generation are the molecular basis of the ″gain-of-function″ cytotoxicity of CNC.

CNC Targets Metabolically Active Cancer Cells

Although OXPHOS is required for both normal and cancer cells, we wondered how specifically CNC targets cancer cells with remarkably lower IC50 and higher therapeutic index (Figure 2a and Figure S2b,d). To elucidate this apparent difference between normal and cancer cells in response to CNC treatment, we generated oncogenically transformed cells by overexpressing the SV40 large T-antigen and mutant (G12V) H-Ras in the normal immortalized human fibroblasts (HFs-hTERT) (Figure S8a,b). We observed a negligible effect of hTERT-driven immortalization on OXPHOS and mitochondria-linked ATP production (Figure 7a,b).

Figure 7

Figure 7. Oncogenic transformation renders cells vulnerable to CNC-induced death. (a) Comparative OCR profiles of HFs (normal parental), HFs-hTERT (normal immortalized), and HFs-hTERT + SV40 + Ras G12V (oncogenically transformed) and effects of mitochondrial inhibitors (oligomycin, FCCP, and rotenone + antimycin) on them (n = 5 biologically independent samples). (b) Bar graphs represent the comparative basal OCR (left; first ∼20 min of respiration), rate of ATP production [middle; ATP production is calculated as (last OCR measurement before oligomycin injection) – (OCR rate measured after oligomycin injection)], and maximal respiratory rate [right; maximal respiratory rate is calculated as (last OCR measurement after oligomycin injection) – (OCR rate measured after FCCP injection)] of HFs (normal parental), HFs-hTERT (normal immortalized), and HFs-hTERT + SV40 + Ras G12V (cancer) cells. All these calculations were done on the experiment presented in panel a. (c) Measurements of total cellular ROS by H2DCFDA staining in the indicated cells in the presence and absence of CNC (n = 3 biologically independent samples). (d) Comparison of cell viability of the indicated cells after 5 days of treatment with CNC (n = 2 biologically independent samples). Note that, in this experiment, we seeded 6 × 103 cells. (e) Measurements of apoptotic cells (<2n nucleus in cell cycle analysis) after 48 h of treatment with CNC of the indicated cells (n = 2 biologically independent samples). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests. *p < 0.05, **p < 0.01.

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The oncogenic transformation of normal human fibroblasts remarkably increases OXPHOS by augmenting the basal OCR, maximal respiratory capacity, and mitochondria-linked ATP production (Figure 7a,b). These results are reminiscent of our earlier findings with a mouse fibroblast cell line showing that transformation by the H-Ras oncogene augments OXPHOS. (57) The CNC-driven inhibition of this hyperactivated OXPHOS specifically generates enhanced ROS in cancer cells compared to the immortalized normal cells (Figure 7c). This finding is further supported by the fact that CNC also generates enhanced ROS in breast cancer cells compared to normal breast epithelial cells (Figure S8c). These cancer cells are remarkably vulnerable to CNC-mediated cytotoxicity and apoptosis (Figure 7d,e), consistent with enhanced CNC-driven ROS generation in these cancer cells. We speculate that cancer cells with an ″OXPHOS-centric″ elevated energy metabolism (57,58) are selectively sensitized to CNC-mediated cytotoxicity.

Discussion

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One of the significant advances emerging from this study is establishing the cellular internalization mechanism of gold-nanocluster systems. Like most cytotoxic nanoparticles described before, our nanoclusters are also internalized into cells by CME. (38,39,59−61) Nevertheless, we did examine the other pathway involved in the uptake of foreign particles by using genistein, an inhibitor of caveolin-mediated endocytosis, and found no disruption of the internalization of CNCs (data not shown). It should be noted that cultured cell lines are a heterogeneous population of cells with respect to cell cycle phases, and it is well-known that cell cycle phases strongly influence endocytic processes. (62,63) Therefore, it can be speculated that those cells with stronger RF from nanoclusters might have internalized more because they happened to be in a cell cycle phase more favorable for endocytosis. This further explains the differential intensities in the staining of cells by nanoclusters in the confocal analyses.
In this study, we also proved that nanoclusters by themselves can induce ROS via blocking OXPHOS but without being excited by an external energy source. Significantly, this ability depends on the ligand used to synthesize the nanocluster system. (64)
CME is an energy-dependent process that requires a continuous supply of ATP to uptake substances into cells. Any alteration in mitochondrial ETC and excessive leakage of protons lead to cytoplasmic acidification. (65) In our case, CNC inhibits the mitochondrial ETC, probably via blocking complex V, resulting in a drop in ATP production and further acidifying the cytoplasm of the cells (Figure 4). Thus, this could be a plausible reason for not showing enhanced differences in the cytotoxicity imparted by CNC beyond a concentration of 200 μg/mL in cancer cells (Figure 2 and Figure S2). We speculate that after the initial uptake of CNC by CME and inhibition of OXPHOS, further internalization of CNC into the cells is impaired due to this negative feedback mechanism.
Our finding that the cytotoxicity of CNC is selective for cancer cells relative to noncancerous cells correlates with the elevated ROS generation (Figures S8c and S2b,d). Normal cells are metabolically less active than cancer cells, and cancer cells have a higher requirement for receptor-ligand recycling via endocytosis. (58) We propose that CNC hijacks this mechanism in cancer cells and it preferentially accumulates in cancer cells, leading to the generation of elevated ROS levels, and shows more pronounced cytotoxicity. (66)
The production of cellular ATP is an essential parameter for maintaining healthy cellular physiology. (41,67) Most of the cellular ATP is produced by mitochondrial OXPHOS. (67) Minimal alterations or disruptions of OXPHOS significantly affect aging and are correlated with various disease conditions, including cancer and neurodegenerative disorders. (68,69) CNC but not GNC interferes explicitly with the mitochondrial ETC, leading to electron leakage and elevated ROS levels. Excessive generation of ROS can chemically damage cellular macromolecules, including DNA, proteins, and lipids, and induce cells to undergo apoptosis. (70,71)
We propose that CNC could be used as an anticancer therapeutic agent based on our discoveries. A key feature of CNC is that it shows selective cytotoxicity toward cancer cells, with an impressive therapeutic window, as evident from our cell-based assays (Figure 2 and Figure S2). However, for future applications, a systematic evaluation is warranted regarding the anticancer activity of CNC, specifically in cancer organoid systems and with cancer models in animals.
The cytotoxicity of water-soluble AuNCs is not only restricted to the Au25(SR)18 nanocluster system since Au18(MPA)14 nanoclusters have also been shown to exhibit some cytotoxic effect toward gram-positive and gram-negative bacteria and since this effect is enhanced in a nanocomposite system with photoporphyrin. (15) In the future, it will indeed be interesting to study the cytotoxic behavior of different magic-numbered AuNCs protected with different water-soluble ligands such as Capt or GSH. It will also be interesting to characterize the conformational states of the ligand Capt in the AuNC system, which may account for the altered topology or physical–chemical properties of Capt in the ligand shell of Au25(Capt)18 compared to free Capt. It has been shown before that similar thiolate ligands such as N-acetyl-l-cysteine and d-penicillamine adsorbed on gold interact in multiple ways with metal surfaces and clusters. (72,73) These studies indicate that, in addition to the thiol group, the carboxylic acid group can also interact with the metal.

Conclusions

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The current study highlights the physicochemical interaction between atomically precise nanoclusters and cells. We demonstrate that different ligands of an atomically precise nanocluster with otherwise identical compositions might trigger different cellular responses. In our experimental model, the atomically precise Au25(SR)18 nanocluster gains cytotoxic property only in the presence of the Capt ligand via inhibition of mitochondrial respiration, whereas the GSH-protected nanocluster does not show such effects.
Our study suggests a plausible mechanism underlying the CNC-induced apoptosis. CNC inhibits the ATP synthase complex (complex V) of the mitochondrial ETC. Mitochondrial respiration inhibitors are toxic to cells by nature, and therefore, CNC might have the potential to be a new member of the broad family of ″mito-poisons″. However, its selectivity toward cancer cells prompts the idea that a specific respiratory or metabolic inhibitor for cancer treatment may be synthesized based on nanoclusters. An exciting outcome of the study is the complete change of target specificity and the biological effect of Capt upon nanocluster formation. Whereas the ligand Capt is used against hypertension, it becomes an anticancer molecule in the form of CNC based on our in vitro cell-based assays. This change of biological function may be related to the altered topology or physical–chemical properties of Capt in the ligand shell of Au25(Capt)18 compared to free Capt. Moreover, in the growing applied field of nanoclusters in biological systems, we need to know whether one can generalize the use of nanoclusters based on their physical properties or whether each nanocluster must be differentiated based on their specific impacts on biological systems. Our study indicates that nanoclusters need to be studied extensively, both physicochemically and biologically, for their compatibility before applying them for any physiological applications.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.2c05054.

  • Supporting figures including fluorescence emission spectra, FTIR spectra, size of the nanocluster, and stability in the cellular medium for CNC/GNC; cytotoxicity of nanocluster toward different cancer and normal cells; wound healing assay in the presence of CNC and Capt; internalization of CNC and GNC into cell and mitochondria; Seahorse assay with free ligand Capt and GSH; and measurement of intracellular ROS on normal and cancer cell lines (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Sarita Roy Bhattacharya - Department of Physical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
    • Kaushik Bhattacharya - Department of Molecular and Cellular Biology, University of Geneva, Sciences III, Geneva 1205, Switzerland
    • Vanessa Joanne Xavier - Department of Molecular and Cellular Biology, University of Geneva, Sciences III, Geneva 1205, Switzerland
    • Abolfazl Ziarati - Department of Physical Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland;  Orcidhttps://orcid.org/0000-0001-6686-4758
  • Author Contributions

    S.R.B. and K.B. contributed equally to this work. They conceived the study, designed and performed experiments, analyzed the data, prepared figures, and wrote the manuscript. V.J.X. generated immortalized and cancer-transformed HFs cells and performed the basic characterization and metabolic profiling assays with them. A.Z. contributed to the experiments with TEM. D.P. and T.B. conceived and supervised the study, contributed to designing experiments and analyzing the data, and wrote and edited the manuscript.

  • Funding

    T.B. and D.P. thank the Swiss National Science Foundation for generous support (grants 200020_172511 and 200020_192232 to T.B. and 31003A_172789/1 to D.P.). D.P. also acknowledges the funding from Canton de Genève and Fondation Medic.

  • Notes
    The authors declare no competing financial interest.

    Original data can be found at: https://doi.org/10.5281/zenodo.6594191.

Acknowledgments

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We acknowledge the confocal facility of the Bioimaging Center and Jérôme Bosset for confocal measurements and the mass spectrometry core facility (MZ 2.0) of the University of Geneva. Lilia Bernasconi and Dina Hany are also kindly acknowledged for technical help in several experiments. We also thank Xianwei Wang for help with the IR studies. We thank Prof. Jean-Claude Martinou for mentoring VJX.

References

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This article references 73 other publications.

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    Srinivasulu, Y. G.; Mozhi, A.; Goswami, N.; Yao, Q.; Xie, J. Gold Nanocluster Based Nanocomposites for Combinatorial Antibacterial Therapy for Eradicating Biofilm Forming Pathogens. Mater. Chem. Front. 2022, 6, 689– 706,  DOI: 10.1039/D1QM00936B
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    McLean, A.; Wang, R.; Huo, Y.; Cooke, A.; Hopkins, T.; Potter, N.; Li, Q.; Isaac, J.; Haidar, J.; Jin, R.; Kopelman, R. Synthesis and Optical Properties of Two-Photon-Absorbing Au25(Captopril)18-Embedded Polyacrylamide Nanoparticles for Cancer Therapy. ACS Appl. Nano Mater. 2020, 3, 1420– 1430,  DOI: 10.1021/acsanm.9b02272
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    16
    Synthesis and Optical Properties of Two-Photon-Absorbing Au25(Captopril)18-Embedded Polyacrylamide Nanoparticles for Cancer Therapy
    McLean, Alan; Wang, Ruofei; Huo, Ying; Cooke, Alexander; Hopkins, Thomas; Potter, Natalie; Li, Qi; Isaac, Joseph; Haidar, Jalal; Jin, Rongchao; Kopelman, Raoul
    ACS Applied Nano Materials (2020), 3 (2), 1420-1430CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    Au25(Captopril)18 nanoclusters (NCs) are a 1.2 nm water-sol. metal nanomaterial with strong two-photon absorption, with excited-state reactive oxygen prodn., and of potential applicability for biomedical imaging and two-photon photodynamic therapy (2p-PDT). Because of the low cellular uptake of Au25(Captopril)18 clusters, its limited potential for conjugation with targeting agents, and to enhance its biocompatibility, we embedded these clusters into hydrogel nanoparticles (NPs) by synthesizing polyacrylamide-encapsulated Au25(Capt)18 nanoparticles (PAAm-Au25(Capt)18 NPs). We verified that the two-photon absorption and singlet oxygen prodn. of these PAAm-Au25 NPs still exhibit the favorable properties of the original metal nanocluster. Furthermore, the Au25-encapsulated polyacrylamide nanoparticles have enhanced in vitro cell uptake, can be easily conjugated to targeting moieties, and exhibit significantly higher biocompatibility. Photoirradn. expts. on HeLa cancer cells incubated with these PAAm-Au25(Capt)18 NPs reveal excellent 2p-PDT efficacy, in contrast to 1p-PDT, thus demonstrating their promising potential for cancer PDT with IR light that penetrates deeply into live tissue.
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  17. 17
    Carlos-Escalante, J. A.; de Jesús-Sánchez, M.; Rivas-Castro, A.; Pichardo-Rojas, P. S.; Arce, C.; Wegman-Ostrosky, T. The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer. Front. Oncol. 2021, 11, 660943  DOI: 10.3389/fonc.2021.660943
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    17
    The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer
    Carlos-Escalante Jose A; de Jesus-Sanchez Marcela; Rivas-Castro Alejandro; Pichardo-Rojas Pavel S; Arce Claudia; Wegman-Ostrosky Talia
    Frontiers in oncology (2021), 11 (), 660943 ISSN:2234-943X.
    Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.
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  18. 18
    Kennedy, L.; Sandhu, J. K.; Harper, M.-E.; Cuperlovic-Culf, M. Role of Glutathione in Cancer: From Mechanisms to Therapies. Biomolecules 2020, 10, 1429,  DOI: 10.3390/biom10101429
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    18
    Role of glutathione in cancer: from mechanisms to therapies
    Kennedy, Luke; Sandhu, Jagdeep K.; Harper, Mary-Ellen; Cuperlovic-Culf, Miroslava
    Biomolecules (2020), 10 (10), 1429CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    A review. Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concns. in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Mol. changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are assocd. with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.
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  19. 19
    Katla, S. K.; Zhang, J.; Castro, E.; Bernal, R. A.; Li, X. Atomically Precise Au25(SG)18 Nanoclusters: Rapid Single-Step Synthesis and Application in Photothermal Therapy. ACS Appl. Mater. Interfaces 2018, 10, 75– 82,  DOI: 10.1021/acsami.7b12614
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    19
    Atomically Precise Au25(SG)18 Nanoclusters: Rapid Single-Step Synthesis and Application in Photothermal Therapy
    Katla, Sai Krishna; Zhang, Jie; Castro, Edison; Bernal, Ricardo A.; Li, XiuJun
    ACS Applied Materials & Interfaces (2018), 10 (1), 75-82CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Remarkable recent advances on Au25(SR)18 nanoclusters have led to significant applications in catalysis, sensing, and magnetism. However, the existing synthetic routes are complicated, particularly for the water-sol. Au25(SG)18 nanoclusters. Here, we report a single-step concn. and temp.-controlled method for rapid synthesis of the Au25(SG)18 nanoclusters in as little as 2 h without the need for low-temp. reaction or even stirring. A systematic time-based investigation was carried out to study the effects of vol., concn., and temp. on the synthesis of these nanoclusters. Further, we discovered for the first time that the Au25(SG)18 nanoclusters exhibit excellent photothermal activities in achieving 100% cell death for MDA-MB-231 breast cancer cells at a power of 10 W/cm2 using an 808 nm laser source, demonstrating applications toward photothermal therapy.
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  20. 20
    Roy Bhattacharya, S.; Bürgi, T. Amplified Vibrational Circular Dichroism as a Manifestation of the Interaction Between a Water Soluble Gold Nanocluster and Cobalt Salt. Nanoscale 2019, 11, 23226– 23233,  DOI: 10.1039/C9NR07534H
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    20
    Amplified vibrational circular dichroism as a manifestation of the interaction between a water soluble gold nanocluster and cobalt salt
    Roy Bhattacharya, Sarita; Burgi, Thomas
    Nanoscale (2019), 11 (48), 23226-23233CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Vibrational CD (VCD) is a powerful tool for the structure detn. of dissolved mols. However, the application of VCD to nanostructures is limited up to now due to the weakness of the effect and hence the low signal intensities. Here we show that the addn. of a small amt. of cobalt(II) drastically enhances the VCD signals of a thiolate-protected gold cluster Au25(Capt)18 (Capt = captopril) in aq. soln. An increase of VCD signal intensity of at least one order of magnitude is obsd. The enhancement depends on the amt. of CoCl2 added but almost an order of magnitude enhancement is already obsd. at a cluster : CoCl2 ratio of 1 : 1. In contrast, CD (CD) and IR spectra hardly change. The increase in VCD intensity goes along with a qual. change of the spectrum and the enhancement increases with time reaching a stable state only after several hours. The enhancement is due to an interaction between the cobalt(II) and the cluster, which also leads to quenching of its fluorescence. The behavior is completely different for free captopril, where the addn. of cobalt(II) salt does not affect the VCD spectrum.
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  21. 21
    Hahn, W. C.; Counter, C. M.; Lundberg, A. S.; Beijersbergen, R. L.; Brooks, M. W.; Weinberg, R. A. Creation of Human Tumour Cells with Defined Genetic Elements. Nature 1999, 400, 464– 468,  DOI: 10.1038/22780
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    21
    Creation of human tumor cells with defined genetic elements
    Hahn, William C.; Counter, Christopher M.; Lundberg, Ante S.; Beijersbergen, Roderick L.; Brooks, Mary W.; Weinberg, Robert A.
    Nature (London) (1999), 400 (6743), 464-468CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
    During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes. However, similar expts. with human cells have consistently failed to yield tumorigenic transformants, indicating a fundamental difference in the biol. of human and rodent cells. The few reported successes in the creation of human tumor cells have depended on the use of chem. or phys. agents to achieve immortalization, the selection of rare, spontaneously arising immortalized cells, or the use of an entire viral genome. The authors show here that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.
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  22. 22
    Jung, K.-J.; Dasgupta, A.; Huang, K.; Jeong, S.-J.; Pise-Masison, C.; Gurova, K. V.; Brady, J. N. Small-Molecule Inhibitor Which Reactivates p53 in Human T-Cell Leukemia Virus Type 1-Transformed Cells. J. Virol. 2008, 82, 8537– 8547,  DOI: 10.1128/JVI.00690-08
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    22
    Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells
    Jung, Kyung-Jin; Dasgupta, Arindam; Huang, Keven; Jeong, Soo-Jin; Pise-Masison, Cynthia; Gurova, Katerina V.; Brady, John N.
    Journal of Virology (2008), 82 (17), 8537-8547CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Human T-cell leukemia virus type 1 (HTLV-1) is the etiol. agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the HTLV-1-encoded Tax protein inhibits the function of tumor suppressor p53 through a Tax-induced NF-κB pathway. Given these attributes, we were interested in the activity of small-mol. inhibitor 9-aminoacridine (9AA), an anticancer drug that targets two important stress response pathways, NF-κB and p53. In the present study, we have examd. the effects of 9AA on HTLV-1-transformed cells. Treatment of HTLV-1-transformed cells with 9AA resulted in a dramatic decrease in cell viability. Consistent with these results, we obsd. an increase in the percentage of cells in sub-G1 and an increase in the no. of cells pos. by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay following treatment of HTLV-1-transformed cells with 9AA. In each assay, HTLV-1-transformed cells C8166, Hut102, and MT2 were more sensitive to treatment with 9AA than control CEM and peripheral blood mononuclear cells. Analyzing p53 function, we demonstrate that treatment of HTLV-1-transformed cells with 9AA resulted in an increase in p53 protein and activation of p53 transcription activity. Of significance, 9AA-induced cell death could be blocked by introduction of a p53 small interfering RNA, linking p53 activity and cell death. These results suggest that Tax-repressed p53 function in HTLV-1-transformed cells is "druggable" and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-κB suggests a promising strategy for the treatment of HTLV-1-transformed cells.
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    Bhattacharya, K.; Weidenauer, L.; Luengo, T. M.; Pieters, E. C.; Echeverría, P. C.; Bernasconi, L.; Wider, D.; Sadian, Y.; Koopman, M. B.; Villemin, M.; Bauer, C.; Rüdiger, S. G. D.; Quadroni, M.; Picard, D. The Hsp70-Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation. Nat. Commun. 2020, 11, 5975,  DOI: 10.1038/s41467-020-19783-w
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    23
    The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation
    Bhattacharya, Kaushik; Weidenauer, Lorenz; Luengo, Tania Moran; Pieters, Ellis C.; Echeverria, Pablo C.; Bernasconi, Lilia; Wider, Diana; Sadian, Yashar; Koopman, Margreet B.; Villemin, Matthieu; Bauer, Christoph; Rudiger, Stefan G. D.; Quadroni, Manfredo; Picard, Didier
    Nature Communications (2020), 11 (1), 5975CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 mol. chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a no. of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70-Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures the proteostatic equil. Thus, cells may act on the level and/or activity of Hop to shift the proteostatic balance between folding and degrdn.
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  24. 24
    Mondal, S.; Bhattacharya, K.; Mandal, C. Nutritional Stress Reprograms Dedifferention in Glioblastoma Multiforme Driven by PTEN/Wnt/Hedgehog Axis: a Stochastic Model of Cancer Stem Cells. Cell Death Discovery 2018, 4, 110,  DOI: 10.1038/s41420-018-0126-6
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    24
    Nutritional stress reprograms dedifferention in glioblastoma multiforme driven by PTEN/Wnt/Hedgehog axis: a stochastic model of cancer stem cells
    Mondal Susmita; Bhattacharya Kaushik; Mandal Chitra; Bhattacharya Kaushik
    Cell death discovery (2018), 4 (), 110 ISSN:2058-7716.
    The emergence and maintenance of cancer stem-like cells (CSCs) are usually governed by tumor niche. Tumor niche always provides metabolic challenges to cancer cells and CSCs mostly because of tissue hypoxia. However, the role of micro-environmental nutritional stress (NS) in dedifferentiation of cancer cells is poorly defined. Here, we developed a stochastic model of CSCs by gradual nutritional deprivation in glioblastoma multiforme (GBM) cells used as a model system. Nutritional deprivation induced enhanced expression of glioblastoma stem-like cells (GSCs)-specific biomarkers with higher invasive and angiogenic properties. This NS-induced cells showed higher xenobiotic efflux ability, and hence exhibit resistance to multiple anticancer drugs. In the molecular level, such NS activated Wnt and Hedgehog (Hh) signaling pathways by stabilizing β-catenin and Gli1, respectively, through modulation of GSK3β/AKT axis. GBM-specific PTEN (phosphatase and tensin homolog) mutation contributed to better phenoconversion toward GSCs. Knocking down of PTEN coupled with NS induction enhanced neurosphere formation, GSC-specific biomarker expressions, and activation of Wnt/Hh signaling. Thus, such an in-depth understanding of dedifferentiation of GBM cells to GSCs under NS suggested that targeting Wnt/Hh signaling possibly be a better therapeutic approach.
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    Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Preibisch, S.; Rueden, C.; Saalfeld, S.; Schmid, B.; Tinevez, J.-Y.; White, D. J.; Hartenstein, V.; Eliceiri, K.; Tomancak, P.; Cardona, A. Fiji: an Open-Source Platform for Biological-Image Analysis. Nat. Methods 2012, 9, 676– 682,  DOI: 10.1038/nmeth.2019
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    Fiji: an open-source platform for biological-image analysis
    Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin; Kaynig, Verena; Longair, Mark; Pietzsch, Tobias; Preibisch, Stephan; Rueden, Curtis; Saalfeld, Stephan; Schmid, Benjamin; Tinevez, Jean-Yves; White, Daniel James; Hartenstein, Volker; Eliceiri, Kevin; Tomancak, Pavel; Cardona, Albert
    Nature Methods (2012), 9 (7_part1), 676-682CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    Fiji is a distribution of the popular open-source software ImageJ focused on biol.-image anal. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biol. research communities.
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    Xie, J.; Pan, X.; Wang, M.; Ma, J.; Fei, Y.; Wang, P.-N.; Mi, L. The Role of Surface Modification for TiO2 Nanoparticles in Cancer Cells. Colloids Surf., B 2016, 143, 148– 155,  DOI: 10.1016/j.colsurfb.2016.03.029
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    The role of surface modification for TiO2 nanoparticles in cancer cells
    Xie, Jin; Pan, Xiaobo; Wang, Mengyan; Ma, Jiong; Fei, Yiyan; Wang, Pei-Nan; Mi, Lan
    Colloids and Surfaces, B: Biointerfaces (2016), 143 (), 148-155CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    Titanium dioxide nanoparticles (TiO2 NPs) have a potential in the field of biol. application. However, its poor dispersibility in water hampered its applications. In this study, 3-phosphonopropionic acid and 3-aminopropyl-triethoxysilane were resp. used for surface modification on TiO2 NPs with neg. and pos. surface charges (denoted as TiO2-COOH and TiO2-NH2). Zeta potentials of the prepd. samples with high abs. value demonstrate the great improvement in their dispersibility. In terms of viability expt., both TiO2-COOH and TiO2-NH2 showed low cytotoxicity. The cellular uptake efficiency and the uptake pathways of TiO2-COOH and TiO2-NH2 for cancer cells were studied. The exocytosis of TiO2-NH2 was also obsd. in the expt.
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  27. 27
    Joshi, A.; Dai, L.; Liu, Y.; Lee, J.; Ghahhari, N. M.; Segala, G.; Beebe, K.; Jenkins, L. M.; Lyons, G. C.; Bernasconi, L.; Tsai, F. T. F.; Agard, D. A.; Neckers, L.; Picard, D. The Mitochondrial HSP90 Paralog TRAP1 Forms an OXPHOS-Regulated Tetramer and is Involved in Mitochondrial Metabolic Homeostasis. BMC Biol. 2020, 18, 10,  DOI: 10.1186/s12915-020-0740-7
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    27
    The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
    Joshi, Abhinav; Dai, Li; Liu, Yanxin; Lee, Jungsoon; Ghahhari, Nastaran Mohammadi; Segala, Gregory; Beebe, Kristin; Jenkins, Lisa M.; Lyons, Gaelyn C.; Bernasconi, Lilia; Tsai, Francis T. F.; Agard, David A.; Neckers, Len; Picard, Didier
    BMC Biology (2020), 18 (1), 10CODEN: BBMIF7; ISSN:1741-7007. (BioMed Central Ltd.)
    Abstr.: Background: The mol. chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metab. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive anal. of the TRAP1 interactome and of how TRAP1 and mitochondrial metab. mutually affect each other. Results: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metab. to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quant. by far, the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline and an increase in OXPHOS. Conclusions: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metab.
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  28. 28
    Yoshida, S.; Tsutsumi, S.; Muhlebach, G.; Sourbier, C.; Lee, M.-J.; Lee, S.; Vartholomaiou, E.; Tatokoro, M.; Beebe, K.; Miyajima, N.; Mohney, R. P.; Chen, Y.; Hasumi, H.; Xu, W.; Fukushima, H.; Nakamura, K.; Koga, F.; Kihara, K.; Trepel, J.; Picard, D.; Neckers, L. Molecular Chaperone TRAP1 Regulates a Metabolic Switch Between Mitochondrial Respiration and Aerobic Glycolysis. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E1604– E1612,  DOI: 10.1073/pnas.1220659110
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    28
    Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis
    Yoshida, Soichiro; Tsutsumi, Shinji; Muhlebach, Guillaume; Sourbier, Carole; Lee, Min-Jung; Lee, Sunmin; Vartholomaiou, Evangelia; Tatokoro, Manabu; Beebe, Kristin; Miyajima, Naoto; Mohney, Robert P.; Chen, Yang; Hasumi, Hisashi; Xu, Wanping; Fukushima, Hiroshi; Nakamura, Ken; Koga, Fumitaka; Kihara, Kazunori; Trepel, Jane; Picard, Didier; Neckers, Leonard
    Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (17), E1604-E1612, SE1604/1-SE1604/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    TRAP1 (TNF receptor-assocd. protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer mol. target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidn., and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metab. is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial mol. chaperone may act as a tumor suppressor.
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    Bhattacharya, K.; Bag, A. K.; Tripathi, R.; Samanta, S. K.; Pal, B. C.; Shaha, C.; Mandal, C. Mahanine, a Novel Mitochondrial Complex-III Inhibitor Induces G0/G1 Arrest Through Redox Alteration-Mediated DNA Damage Response and Regresses Glioblastoma Multiforme. Am. J. Cancer Res. 2014, 4, 629– 647
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    29
    Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme
    Bhattacharya Kaushik; Bag Arup K; Samanta Suman K; Mandal Chitra; Tripathi Rakshamani; Shaha Chandrima; Pal Bikas C
    American journal of cancer research (2014), 4 (6), 629-47 ISSN:2156-6976.
    The Electron transport chain (ETC) is responsible for oxidative phosphorylation-mediated mitochondrial respiration. Here we wanted to address the mahanine-induced targeted pathways in glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated mahanine, as a novel mitochondrial complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of mahanine. During G0/G1 arrest, other hallmark proteins like, cyclin D1/cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of mahanine was also established in in vivo mice model. Mahanine-induced complex-III inhibition triggered enhanced ROS in hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that mahanine-treated G0/G1 arrested cells were less potent to form xenograft tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage. Taken together, our results established that complex-III of ETC is one of the possible potential targets of mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes.
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  30. 30
    Tofanelli, M. A.; Ackerson, C. J. Superatom Electron Configuration Predicts Thermal Stability of Au25(SR)18 Nanoclusters. J. Am. Chem. Soc. 2012, 134, 16937– 16940,  DOI: 10.1021/ja3072644
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    Superatom Electron Configuration Predicts Thermal Stability of Au25(SR)18 Nanoclusters
    Tofanelli, Marcus A.; Ackerson, Christopher J.
    Journal of the American Chemical Society (2012), 134 (41), 16937-16940CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The exceptional stability of ligand-stabilized gold nanoclusters such as Au25(SC6H13)18-, Au39(PR3)14X6-, and Au102(SR)44 arises from the total filling of superat. electron shells, resulting in a "noble-gas superatom" electron configuration. Electrochem. manipulation of the oxidn. state can add or remove electrons from superatom orbitals, creating species electronically analogous to at. radicals. Herein we show that oxidizing the Au25(SR)18- superatom from the noble-gas-like 1S21P6 electron configuration to the open-shell radical 1S21P5 and diradical 1S21P4 configurations results in decreased thermal stability of the compd., as measured by differential scanning calorimetry. Similar expts. probing five oxidn. states of the putatively geometrically stabilized Au144(SR)60 cluster suggest a more complex relationship between oxidn. state and thermal stability for this compd.
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    Tofanelli, M. A.; Salorinne, K.; Ni, T. W.; Malola, S.; Newell, B.; Phillips, B.; Häkkinen, H.; Ackerson, C. J. Jahn–Teller Effects in Au25(SR)18. Chem. Sci. 2016, 7, 1882– 1890,  DOI: 10.1039/C5SC02134K
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    Jahn-Teller effects in Au25(SR)18
    Tofanelli, Marcus A.; Salorinne, Kirsi; Ni, Thomas W.; Malola, Sami; Newell, Brian; Phillips, Billy; Hakkinen, Hannu; Ackerson, Christopher J.
    Chemical Science (2016), 7 (3), 1882-1890CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A review. The relationship between oxidn. state, structure, and magnetism in many mols. is well described by first-order Jahn-Teller distortions. This relationship is not yet well defined for ligated nanoclusters and nanoparticles, esp. the nano-technol. relevant gold-thiolate protected metal clusters. Here we interrogate the relationships between structure, magnetism, and oxidn. state for the three stable oxidn. states, -1, 0 and +1 of the thiolate protected nanocluster Au25(SR)18. We present the single crystal X-ray structures of the previously undetd. charge state Au25(SR)18+1, as well as a higher quality single crystal structure of the neutral compd. Au25(SR)180. Structural data combined with SQUID magnetometry and DFT theory enable a complete description of the optical and magnetic properties of Au25(SR)18 in the three oxidn. states. In aggregate the data suggests a first-order Jahn-Teller distortion in this compd. The high quality single crystal X-ray structure enables an anal. of the ligand-ligand and ligand-cluster packing interactions that underlie single-crystal formation in thiolate protected metal clusters.
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  32. 32
    Shibu, E. S.; Muhammed, M. A. H.; Tsukuda, T.; Pradeep, T. J. Phys. Chem. C 2008, 112, 12168– 12176,  DOI: 10.1021/jp800508d
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    32
    Ligand Exchange of Au25SG18 Leading to Functionalized Gold Clusters: Spectroscopy, Kinetics, and Luminescence
    Shibu, E. S.; Muhammed, M. A. Habeeb; Tsukuda, T.; Pradeep, T.
    Journal of Physical Chemistry C (2008), 112 (32), 12168-12176CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Ligand exchange offers an effective way to modify the properties of the recently prepd. quantum clusters of Au. To tune optical and photoluminescence properties of one of the most stable quantum clusters of Au, Au25SG18 (SG-glutathione thiolate), the authors functionalized it by the exchange of -SG with functionalized -SG and with an altogether different ligand, namely, 3-mercapto-2-butanol (MB). The products were characterized by various techniques such as optical absorption (UV-visible), FTIR, NMR, x-ray photoelectron (XPS), and luminescence spectroscopies, mass spectrometry, and TG. Analyses of the TG data helped to establish the mol. compn. of the products. Ligand exchange reaction was monitored by NMR spectroscopy, and the exchange reaction follows a 1st order kinetics. The XPS study showed that after the exchange reaction there was no change in the chem. nature of the metal core and binding energy values of Au 4f7/2 and 4f5/2, which are similar in both the parent and the exchanged products. Photoluminescence studies of these clusters, done in the aerated conditions, showed that the excitation spectrum of the MB-exchanged product is entirely different from the acetyl- and formyl-glutathione exchanged products. The inherent fluorescence and solid-state emission of these clusters were obsd. This intense emission allows optical imaging of the material in the solid state. The emission is strongly temp. dependent. The synthesis of a diverse variety of clusters and their chem. stability and intense luminescence offer numerous applications in areas such as energy transfer, sensors, biolabeling, and drug delivery.
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    Tay, C. Y.; Yu, Y.; Setyawati, M. I.; Xie, J.; Leong, D. T. Presentation Matters: Identity of Gold Nanocluster Capping Agent Governs Intracellular Uptake and Cell Metabolism. Nano Res. 2014, 7, 805– 815,  DOI: 10.1007/s12274-014-0441-z
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    Presentation matters: Identity of gold nanocluster capping agent governs intracellular uptake and cell metabolism
    Tay, Chor Yong; Yu, Yong; Setyawati, Magdiel Inggrid; Xie, Jianping; Leong, David Tai
    Nano Research (2014), 7 (6), 805-815CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
    Au nanoclusters (AuNCs) hold tremendous potential to be employed in a wide variety of biol. applications. Despite the rapid development in the field of NCs synthesis, a comprehensive understanding of how cells interact with this class of ultra-small nanoparticles (<2 nm) having defined sizes and surface chem., remains poorly understood. In this study, we show that the choice of the surface ligand used to protect AuNCs can significantly perturb cellular uptake and intracellular redox signaling. A panel of monodisperse, atomically precise AuNCs with different core Au atom no. (i.e., Au15, Au18 and Au25) protected with either mercaptopropionic acid (MPA) or glutathione (GSH) capping agent were synthesized and their effects on the generation of intracellular reactive oxygen species (ROS), cytotoxicity and genotoxicity of the NCs were assessed. Both mitochondrial superoxide anion (O2·-) and cytoplasmic ROS were found to be higher in cells exposed to MPA but not GSH capped AuNCs. The unregulated state of intracellular ROS is correlated to the amt. of internalized AuNCs. Interestingly, MPA-AuNCs induction of ROS level did not lead to any detrimental cellular effects such as cell death or DNA damage. Instead, it was obsd. that the increase in redox status corresponded to higher cellular metab. and proliferative capacity. Our study illustrates that surface chem. of AuNCs plays a pivotal role in affecting the biol. outcomes and the new insights gained will be useful to form the basis of defining specific design rules to enable rational engineering of ultra-small complex nanostructures for biol. applications. [Figure not available: see fulltext.].
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    Sabuncu, A. C.; Grubbs, J.; Qian, S.; Abdel-Fattah, T. M.; Stacey, M. W.; Beskok, A. Probing Nanoparticle Interactions in Cell Culture Media. Colloids Surf., B 2012, 95, 96– 102,  DOI: 10.1016/j.colsurfb.2012.02.022
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    Probing nanoparticle interactions in cell culture media
    Sabuncu, Ahmet C.; Grubbs, Janna; Qian, Shizhi; Abdel-Fattah, Tarek M.; Stacey, Michael W.; Beskok, Ali
    Colloids and Surfaces, B: Biointerfaces (2012), 95 (), 96-102CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    Nanoparticle research is often performed in vitro with little emphasis on the potential role of cell culture medium. In this study, gold nanoparticle interactions with cell culture medium and 2 cancer cell lines (human T-cell leukemia Jurkat and human pancreatic carcinoma PANC1) were investigated. Gold nanoparticles of 10, 25, 50, and 100 nm in diam. at fixed mass concn. were tested. Size distributions and zeta potentials of gold nanoparticles suspended in deionized (DI) water and Dulbecco's Modified Eagle's Media (DMEM) supplemented with fetal calf serum (FCS) were measured using dynamic light scattering (DLS) technique. In DI water, particle size distributions exhibited peaks around their nominal diams. However, the gold nanoparticles suspended in DMEM supplemented with FCS formed complexes around 100 nm, regardless of their nominal sizes. The DLS and UV-vis spectroscopy results indicate gold nanoparticle agglomeration in DMEM that is not supplemented by FCS. The zeta potential results indicate that protein rich FCS increases the dispersion quality of gold nanoparticle suspensions through steric effects. Cellular uptake of 25 and 50 nm gold nanoparticles by Jurkat and PANC1 cell lines were investigated using inductively coupled plasma-mass spectroscopy. The intracellular gold level of PANC1 cells was higher than that of Jurkat cells, where 50 nm particles enter cells at faster rates than the 25 nm particles.
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    Wang, M.; Wu, Z.; Yang, J.; Wang, G.; Wang, H.; Cai, W. Au25(SG)18 as a Fluorescent Iodide Sensor. Nanoscale 2012, 4, 4087– 4090,  DOI: 10.1039/c2nr30169e
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    Au25(SG)18 as a fluorescent iodide sensor
    Wang, Man; Wu, Zhikun; Yang, Jiao; Wang, Guozhong; Wang, Hongzhi; Cai, Weiping
    Nanoscale (2012), 4 (14), 4087-4090CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    The recently emerging gold nanoclusters (GNC) are of major importance for both basic science studies and practical applications. Based on its surface-induced fluorescence properties, the potential use of Au25(SG)18 (GSH: glutathione) as a fluorescent iodide sensor was studied. The current detection limit of 400 nM, which can possibly be further enhanced by optimizing the conditions, and excellent selectivity among 12 types of anions (F-, Cl-, Br-, I-, NO3-, ClO4-, HCO3-, IO3-, SO42-, SO32-, AcO- and C6H5O73-) make Au25(SG)18 a good candidate for iodide sensing. Also, the work revealed the particular sensing mechanism, which is affinity-induced ratiometric and enhanced fluorescence (abbreviated to AIREF), which has rarely been reported previously and may provide an alternative strategy for devising nanoparticle-based sensors.
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    Dalal, C.; Saha, A.; Jana, N. R. Nanoparticle Multivalency Directed Shifting of Cellular Uptake Mechanism. J. Phys. Chem. C 2016, 120, 6778– 6786,  DOI: 10.1021/acs.jpcc.5b11059
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    Nanoparticle Multivalency Directed Shifting of Cellular Uptake Mechanism
    Dalal, Chumki; Saha, Arindam; Jana, Nikhil R.
    Journal of Physical Chemistry C (2016), 120 (12), 6778-6786CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Although nanoparticle multivalency is known to influence their biol. labeling performance, the functional role of multivalency is largely unexplored. Here we show that the folate receptor mediated cellular internalization mechanism of 35-50 nm nanoparticle shifts from caveolae- to clathrin-mediated endocytosis as the nanoparticle multivalency increases from 10 to 40 and results in the difference of their subcellular trafficking. We have synthesized folate functionalized multivalent quantum dot (QD) with varied av. nos. of folate per QD between 10 and 110 [e.g., QD(folate)10, QD(folate)20, QD(folate)40, QD(folate)110] and investigated their uptake and localization into folate receptor overexpressed HeLa and KB cells. We found that uptake of QD(folate)10 occurs predominantly via caveolae-mediated endocytosis and entirely trafficked to the perinuclear region. In contrast, uptake of QD(folate)20 occurs via both caveolae- and chathrin-mediated endocytosis; uptake of QD(folate)40 and QD(folate)110 occurs predominantly via clathrin-mediated endocytosis and these three QDs localize predominantly at lysosome with restricted trafficking to the perinuclear region. This work shows the functional role of multivalent interaction in cellular endocytosis and intracellular trafficking which can be exploited for subcellular targeting applications.
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    Bera, K.; Maiti, S.; Maity, M.; Mandal, C.; Maiti, N. C. Porphyrin–Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells. ACS Omega 2018, 3, 4602– 4619,  DOI: 10.1021/acsomega.8b00419
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    Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells
    Bera, Kaushik; Maiti, Samarpan; Maity, Mritunjoy; Mandal, Chitra; Maiti, Nakul C.
    ACS Omega (2018), 3 (4), 4602-4619CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with a tetrasodium salt of meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles. Porphyrin interacts with the gold nanosurface through the coordination interaction between gold and pyrrolic nitrogen atoms of the porphyrin and forms a strong assocn. complex. DOX-loaded nanocomposite DOX@TPPS-AuNPs demonstrated enhanced cellular uptake with significantly reduced drug efflux in MDR brain cancer cells, thereby increasing the retention time of the drug within tumor cells. It exhibited about 9 times greater potency for cellular apoptosis via triggered release commenced by acidic pH. DOX has been successfully loaded on the porphyrin-modified gold nanosurface noncovalently with high encapsulation efficacy (∼90%) and tightly assocd. under normal physiol. conditions but capable of releasing ∼81% of drug in a low-pH environment. Subsequently, DOX-loaded TPPS-AuNPs exhibited higher inhibition of cellular metastasis, invasion, and angiogenesis, suggesting that TPPS-modified AuNPs could improve the therapeutic efficacy of the drug mol. Unlike free DOX, drug-loaded TPPS-AuNPs did not show toxicity toward normal cells. Therefore, higher drug encapsulation efficacy with selective targeting potential and acidic-pH-mediated intracellular release of DOX at the nucleus make TPPS-AuNPs a "magic bullet" for implication in nanomedicine.
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    Von Kleist, L.; Stahlschmidt, W.; Bulut, H.; Gromova, K.; Puchkov, D.; Robertson, M. J.; MacGregor, K. A.; Tomilin, N.; Pechstein, A.; Chau, N.; Chircop, M.; Sakoff, J.; Peter von Kries, J.; Saenger, W.; Kräusslich, H.-G.; Shupliakov, O.; Robinson, P. J.; McCluskey, A.; Haucke, V. Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition. Cell 2011, 146, 841,  DOI: 10.1016/j.cell.2011.08.014
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    Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition [Erratum to document cited in CA155:427405]
    von Kleist, Lisa; Stahlschmidt, Wiebke; Bulut, Haydar; Gromova, Kira; Puchkov, Dmytro; Robertson, Mark J.; MacGregor, Kylie A.; Tomilin, Nikolay; Pechstein, Arndt; Chau, Ngoc; Chircop, Megan; Sakoff, Jennette; Peter von Kries, Jens; Saenger, Wolfram; Kraeusslich, Hans-Georg; Shupliakov, Oleg; Robinson, Phillip J.; McCluskey, Adam; Haucke, Volker
    Cell (Cambridge, MA, United States) (2011), 146 (5), 841CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    On page 471, the eighth author's name contained an error; the cor. author list is given.
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    Preta, G.; Cronin, J. G.; Sheldon, I. M. Dynasore - Not Just a Dynamin Inhibitor. Cell Commun. Signaling 2015, 13, 24,  DOI: 10.1186/s12964-015-0102-1
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    Dynasore - not just a dynamin inhibitor
    Preta Giulio; Cronin James G; Sheldon I Martin
    Cell communication and signaling : CCS (2015), 13 (), 24 ISSN:.
    Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals evidence that dynasore reduces labile cholesterol in the plasma membrane, and disrupts lipid raft organization, in a dynamin-independent manner. To explore the role of dynamin it is important to use multiple dynamin inhibitors, alongside the use of dynamin mutants and RNA interference targeting genes encoding dynamin. On the other hand, dynasore provides an interesting tool to explore the regulation of cholesterol in plasma membranes.
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    Kuhn, D. A.; Vanhecke, D.; Michen, B.; Blank, F.; Gehr, P.; Petri-Fink, A.; Rothen-Rutishauser, B. Different Endocytotic Uptake Mechanisms for Nanoparticles in Epithelial Cells and Macrophages. Beilstein J. Nanotechnol. 2014, 5, 1625– 1636,  DOI: 10.3762/bjnano.5.174
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    Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages
    Kuhn, Dagmar A.; Vanhecke, Dimitri; Michen, Benjamin; Blank, Fabian; Gehr, Peter; Petri-Fink, Alke; Rothen-Rutishauser, Barbara
    Beilstein Journal of Nanotechnology (2014), 5 (), 1625-1636, 12 pp.CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
    Precise knowledge regarding cellular uptake of nanoparticles is of great importance for future biomedical applications. Four different endocytotic uptake mechanisms, i.e., phagocytosis, macropinocytosis, clathrin- and caveolin-mediated endocytosis, were investigated using a mouse macrophage (J774A.1) and a human alveolar epithelial type II cell line (A549). In order to deduce the involved pathway in nanoparticle uptake, selected inhibitors specific for one of the endocytotic pathways were optimized regarding concn. and incubation time in combination with fluorescently tagged marker proteins. Qual. immunolocalization showed that J774A.1 cells highly expressed the lipid raft-related protein flotillin-1 and clathrin heavy chain, however, no caveolin-1. A549 cells expressed clathrin heavy chain and caveolin-1, but no flotillin-1 uptake-related proteins. Our data revealed an impeded uptake of 40 nm polystyrene nanoparticles by J774A.1 macrophages when actin polymn. and clathrin-coated pit formation was blocked. From this result, it is suggested that macropinocytosis and phagocytosis, as well as clathrin-mediated endocytosis, play a crucial role. The uptake of 40 nm nanoparticles in alveolar epithelial A549 cells was inhibited after depletion of cholesterol in the plasma membrane (preventing caveolin-mediated endocytosis) and inhibition of clathrin-coated vesicles (preventing clathrin-mediated endocytosis). Our data showed that a combination of several distinguishable endocytotic uptake mechanisms are involved in the uptake of 40 nm polystyrene nanoparticles in both the macrophage and epithelial cell line.
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    Nolfi-Donegan, D.; Braganza, A.; Shiva, S. Mitochondrial Electron Transport Chain: Oxidative Phosphorylation, Oxidant Production, and Methods of Measurement. Redox Biol. 2020, 37, 101674  DOI: 10.1016/j.redox.2020.101674
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    Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement
    Nolfi-Donegan, Deirdre; Braganza, Andrea; Shiva, Sruti
    Redox Biology (2020), 37 (), 101674CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
    A review. The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of electron transfer is the generation of reactive oxygen species (ROS), which contributes to both homeostatic signaling as well as oxidative stress during pathol. In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS prodn. by the electron transport chain. We also outline traditional and novel translational methodol. for assessing mitochondrial energetics in health and disease.
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    Zhao, Y.; Butler, E. B.; Tan, M. Targeting Cellular Metabolism to Improve Cancer Therapeutics. Cell Death Discovery 2013, 4, e532  DOI: 10.1038/cddis.2013.60
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    Targeting cellular metabolism to improve cancer therapeutics
    Zhao, Y.; Butler, E. B.; Tan, M.
    Cell Death & Disease (2013), 4 (March), e532CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
    A review. The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy prodn. in cancer cells is abnormally dependent on aerobic glycolysis. In addn. to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metab. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metab., fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metab. may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metab. inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metab. in therapeutic resistance, which is a highly clin. relevant area in cancer metab. research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metab. and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
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    Guo, R.; Gu, J.; Zong, S.; Wu, M.; Yang, M. Structure and Mechanism of Mitochondrial Electron Transport Chain. Biomed. J. 2018, 41, 9– 20,  DOI: 10.1016/j.bj.2017.12.001
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    Structure and mechanism of mitochondrial electron transport chain
    Guo Runyu; Gu Jinke; Zong Shuai; Wu Meng; Yang Maojun
    Biomedical journal (2018), 41 (1), 9-20 ISSN:.
    Respiration is one of the most vital and basic features of living organisms. In mammals, respiration is accomplished by respiratory chain complexes located on the mitochondrial inner membrane. In the past century, scientists put tremendous efforts in understanding these complexes, but failed to solve the high resolution structure until recently. In 2016, three research groups reported the structure of respiratory chain supercomplex from different species, and fortunately the structure solved by our group has the highest resolution. In this review, we will compare the recently solved structures of respirasome, probe into the relationship between cristae shape and respiratory chain organization, and discuss the highly disputed issues afterwards. Besides, our group reported the first high resolution structure of respirasome and medium resolution structure of megacomplex from cultured human cells this year. Definitely, these supercomplex structures will provide precious information for conquering the mitochondrial malfunction diseases.
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    Zhao, R. Z.; Jiang, S.; Zhang, L.; Yu, Z.-B. Mitochondrial Electron Transport Chain, ROS Generation and Uncoupling (Review). Int. J. Mol. Med. 2019, 44, 3– 15,  DOI: 10.3892/ijmm.2019.4188
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    Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
    Zhao, Ru-zhou; Jiang, Shuai; Zhang, Lin; Yu, Zhi-bin
    International Journal of Molecular Medicine (2019), 44 (1), 3-15CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)
    A review. The mammalian mitochondrial electron transport chain (ETC) includes complexes I-IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I-IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiol. and pathol. regulation of ROS. As signaling mols., ROS play an important role in cell proliferation, hypoxia adaptation and cell fate detn., but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a no. of diseases are closely related to ROS overprodn. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1-5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temp. in a cold environment through non-shivering thermogenesis. The core role of UCP2-5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are assocd. with UCPs.
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    Yépez, V. A.; Kremer, L. S.; Iuso, A.; Gusic, M.; Kopajtich, R.; Koňaříková, E.; Nadel, A.; Wachutka, L.; Prokisch, H.; Gagneur, J. OCR-Stats: Robust Estimation and Statistical Testing of Mitochondrial Respiration Activities Using Seahorse XF Analyzer. PLoS One 2018, 13, e0199938  DOI: 10.1371/journal.pone.0199938
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    OCR-Stats: robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer
    Yepez, Vicente A.; Kremer, Laura S.; Iuso, Arcangela; Gusic, Mirjana; Kopajtich, Robert; Konarikova, Elisaka; Nadel, Agnieszka; Wachutka, Leonhard; Prokisch, Holger; Gagneur, Julien
    PLoS One (2018), 13 (7), e0199938/1-e0199938/18CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The accurate quantification of cellular and mitochondrial bioenergetic activity is of great interest in medicine and biol. Mitochondrial stress tests performed with Seahorse Bioscience XF Analyzers allow the estn. of different bioenergetic measures by monitoring the oxygen consumption rates (OCR) of living cells in multi-well plates. However, studies of the statistical best practices for detg. aggregated OCR measurements and comparisons have been lacking. Therefore, to understand how OCR behaves across different biol. samples, wells, and plates, we performed mitochondrial stress tests in 126 96-well plates involving 203 fibroblast cell lines. We show that the noise of OCR is multiplicative, that outlier data points can concern individual measurements or all measurements of a well, and that the inter-plate variation is greater than the intra-plate variation. Based on these insights, we developed a novel statistical method, OCR-Stats, that: (i) robustly ests. OCR levels modeling multiplicative noise and automatically identifying outlier data points and outlier wells; and (ii) performs statistical testing between samples, taking into account the different magnitudes of the between- and within-plate variations. This led to a significant redn. of the coeff. of variation across plates of basal respiration by 45% and of maximal respiration by 29%. Moreover, using pos. and neg. controls, we show that our statistical test outperforms the existing methods.
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    Pike Winer, L. S.; Wu, M. Rapid Analysis of Glycolytic and Oxidative Substrate Flux of Cancer Cells in a Microplate. PLoS One 2014, 9, e109916  DOI: 10.1371/journal.pone.0109916
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    Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate
    Pike Winer, Lisa S.; Wu, Min
    PLoS One (2014), 9 (10), e109916/1-e109916/14, 14 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Cancer cells exhibit remarkable alterations in cellular metab., particularly in their nutrient substrate preference. We have devised several exptl. methods that rapidly analyze the metabolic substrate flux in cancer cells: glycolysis and the oxidn. of major fuel substrates glucose, glutamine, and fatty acids. Using the XF Extracellular Flux analyzer, these methods measure, in real-time, the oxygen consumption rate OCR and extracellular acidification rate ECAR of living cells in a microplate as they respond to substrates and metabolic perturbation agents. In proof-of-principle expts., we analyzed substrate flux and mitochondrial bioenergetics of two human glioblastoma cell lines, SF188s and SF188f, which were derived from the same parental cell line but proliferate at slow and fast rates, resp. These analyses led to three interesting observations: (1) both cell lines respired effectively with substantial endogenous substrate respiration; (2) SF188f cells underwent a significant shift from glycolytic to oxidative metab., along with a high rate of glutamine oxidn. relative to SF188s cells; and (3) the mitochondrial proton leak-linked respiration of SF188f cells increased significantly compared to SF188s cells. It is plausible that the proton leak of SF188f cells may play a role in allowing continuous glutamine-fueled anaplerotic TCA cycle flux by partially uncoupling the TCA cycle from oxidative phosphorylation. Taken together, these rapid, sensitive and high-throughput substrate flux anal. methods introduce highly valuable approaches for developing a greater understanding of genetic and epigenetic pathways that regulate cellular metab., and the development of therapies that target cancer metab.
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    Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J. S.; Hileman, E. O.; Plunkett, W.; Keating, M. J.; Huang, P. Inhibition of Mitochondrial Respiration: a Novel Strategy to Enhance Drug-Induced Apoptosis in Human Leukemia Cells by a Reactive Oxygen Species-Mediated Mechanism. J. Biol. Chem. 2003, 278, 37832– 37839,  DOI: 10.1074/jbc.M301546200
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    Inhibition of Mitochondrial Respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism
    Pelicano, Helene; Feng, Li; Zhou, Yan; Carew, Jennifer S.; Hileman, Elizabeth O.; Plunkett, William; Keating, Michael J.; Huang, Peng
    Journal of Biological Chemistry (2003), 278 (39), 37832-37839CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Cancer cells are under intrinsic increased oxidative stress and vulnerable to free radical-induced apoptosis. Here, the authors report a strategy to hinder mitochondrial electron transport and increase superoxide radical generation in human leukemia cells as a novel mechanism to enhance apoptosis induced by anticancer agents. This strategy was first tested in a proof-of-principle study using rotenone, a specific inhibitor of mitochondrial electron transport complex I. Partial inhibition of mitochondrial respiration enhances electron leakage from the transport chain, leading to an increase in generation and sensitization of the leukemia cells to anticancer agents whose action involve free radical generation. Using leukemia cells with genetic alterations in mitochondrial DNA and biochem. approaches, the authors further demonstrated that As2O3, a clin. active anti-leukemia agent, inhibits mitochondrial respiratory function, increases free radical generation, and enhances the activity of another agent against cultured leukemia cells and primary leukemia cells isolated from patients. The authors study shows that interfering mitochondrial respiration is a novel mechanism by which As2O3 increases generation of free radicals. This novel mechanism of action provides a biochem. basis for developing new drug combination strategies using As2O3 to enhance the activity of anticancer agents by promoting generation of free radicals.
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    Kausar, S.; Wang, F.; Cui, H. The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases. Cell 2018, 7, 274,  DOI: 10.3390/cells7120274
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    The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases
    Kausar, Saima; Wang, Feng; Cui, Hongjuan
    Cells (2018), 7 (12), 274CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
    Mitochondria are dynamic cellular organelles that consistently migrate, fuse, and divide to modulate their no., size, and shape. In addn., they produce ATP, reactive oxygen species, and also have a biol. role in antioxidant activities and Ca2+ buffering. Mitochondria are thought to play a crucial biol. role in most neurodegenerative disorders. Neurons, being high-energy-demanding cells, are closely related to the maintenance, dynamics, and functions of mitochondria. Thus, impairment of mitochondrial activities is assocd. with neurodegenerative diseases, pointing to the significance of mitochondrial functions in normal cell physiol. In recent years, considerable progress has been made in our knowledge of mitochondrial functions, which has raised interest in defining the involvement of mitochondrial dysfunction in neurodegenerative diseases. Here, we summarize the existing knowledge of the mitochondrial function in reactive oxygen species generation and its involvement in the development of neurodegenerative diseases.
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    Zorov, D. B.; Juhaszova, M.; Sollott, S. J. Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release. Physiol. Rev. 2014, 94, 909– 950,  DOI: 10.1152/physrev.00026.2013
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    Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release
    Zorov, Dmitry B.; Juhaszova, Magdalena; Sollott, Steven J.
    Physiological Reviews (2014), 94 (3), 909-950CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
    A review. Byproducts of normal mitochondrial metab. and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiol. role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-assocd. ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiol. role by removal of unwanted cells or damaged mitochondria, or cause the pathol. elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS prodn. in vivo.
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    Hu, L.; Han, S.; Parveen, S.; Yuan, Y.; Zhang, L.; Xu, G. Highly Sensitive Fluorescent Detection of Trypsin Based on BSA-Stabilized Gold Nanoclusters. Biosens. Bioelectron. 2012, 32, 297– 299,  DOI: 10.1016/j.bios.2011.12.007
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    Highly sensitive fluorescent detection of trypsin based on BSA-stabilized gold nanoclusters
    Hu, Lianzhe; Han, Shuang; Parveen, Saima; Yuan, Yali; Zhang, Ling; Xu, Guobao
    Biosensors & Bioelectronics (2012), 32 (1), 297-299CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    In this study, fluorescent metal nanoclusters are presented as novel probes for sensitive detection of protease for the first time. The sensing mechanism is based on trypsin digestion of the protein template of BSA-stabilized Au nanoclusters. The decrease in fluorescence intensity of BSA-Au nanoclusters caused by trypsin allows the sensitive detection of trypsin in the range of 0.01-100 μg/mL. The detection limit for trypsin is 2 ng/mL (86 pM) at a signal-to-noise ratio of 3. The present nanosensor for trypsin detection possesses red emission, excellent biocompatibility, high selectivity, and good stability. In addn., we demonstrated the application of the present approach in real urine samples, which suggested its potential for diagnostic purposes.
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    McDonagh, B. H.; Singh, G.; Bandyopadhyay, S.; Lystvet, S. M.; Ryan, J. A.; Volden, S.; Kim, E.; Sandvig, I.; Sandvig, A.; Glomm, W. R. Controlling the Self-Assembly and Optical Properties of Gold Nanoclusters and Gold Nanoparticles Biomineralized with Bovine Serum Albumin. RSC Adv. 2015, 5, 101101– 101109,  DOI: 10.1039/C5RA23423A
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    Controlling the self-assembly and optical properties of gold nanoclusters and gold nanoparticles biomineralized with bovine serum albumin
    McDonagh, Birgitte H.; Singh, Gurvinder; Bandyopadhyay, Sulalit; Lystvet, Sina M.; Ryan, Joseph A.; Volden, Sondre; Kim, Eugene; Sandvig, Ioanna; Sandvig, Axel; Glomm, Wilhelm R.
    RSC Advances (2015), 5 (122), 101101-101109CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    While the size-dependent optical properties of BSA-stabilized gold nanoclusters are well known, the time-dependent growth mechanism remains to be described. Herein, we systematically compare two synthesis methods with and without ascorbic acid, and show that tuning of BSA-stabilized gold nanoclusters (AuNCs) of different sizes can be performed without the aid of an extrinsic reducing agent and with good reproducibility. We also show that adding ascorbic acid yields larger BSA-stabilized gold nanoparticles (AuNPs), and that AuNPs can only form above a threshold gold precursor concn. Using computed tomog., we describe how these biomineralized AuNPs show size-dependent X-ray attenuation. Growth of BSA-stabilized AuNCs and AuNPs, over a range of gold precursor concns., was followed with steady-state fluorescence and UV-vis spectroscopy for one week, constituting the first study of its kind. Based on our results, we propose a mechanism for BSA-stabilization of AuNCs and AuNPs that can further aid in selective growth of discrete AuNCs and AuNPs.
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    Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in Cancer Therapy: The Bright Side of the Moon. Exp. Mol. Med. 2020, 52, 192– 203,  DOI: 10.1038/s12276-020-0384-2
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    ROS in cancer therapy: the bright side of the moon
    Perillo, Bruno; Di Donato, Marzia; Pezone, Antonio; Di Zazzo, Erika; Giovannelli, Pia; Galasso, Giovanni; Castoria, Gabriella; Migliaccio, Antimo
    Experimental & Molecular Medicine (2020), 52 (2), 192-203CODEN: EMMEF3; ISSN:2092-6413. (Nature Research)
    A review. Reactive oxygen species constitute a group of highly reactive mols. that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The prodn. of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymic and nonenzymic pathways in the same cells. Moderate increases of ROS contribute to several pathol. conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the mol. mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.
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    Yang, H.; Villani, R. M.; Wang, H.; Simpson, M. J.; Roberts, M. S.; Tang, M.; Liang, X. The Role of Cellular Reactive Oxygen Species in Cancer Chemotherapy. J. Exp. Clin. Cancer Res. 2018, 37, 266,  DOI: 10.1186/s13046-018-0909-x
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    The role of cellular reactive oxygen species in cancer chemotherapy
    Yang, Haotian; Villani, Rehan M.; Wang, Haolu; Simpson, Matthew J.; Roberts, Michael S.; Tang, Min; Liang, Xiaowen
    Journal of Experimental & Clinical Cancer Research (2018), 37 (), 266CODEN: JECRDN; ISSN:1756-9966. (BioMed Central Ltd.)
    A review. Most chemotherapeutics elevate intracellular levels of reactive oxygen species (ROS), and many can alter redox-homeostasis of cancer cells. It is widely accepted that the anticancer effect of these chemotherapeutics is due to the induction of oxidative stress and ROS-mediated cell injury in cancer. However, various new therapeutic approaches targeting intracellular ROS levels have yielded mixed results. Since it is impossible to quant. detect dynamic ROS levels in tumors during and after chemotherapy in clin. settings, it is of increasing interest to apply math. modeling techniques to predict ROS levels for understanding complex tumor biol. during chemotherapy. This outlines the current understanding of the role of ROS in cancer cells during carcinogenesis and during chemotherapy, provides a crit. anal. of the methods used for quant. ROS detection and discusses the application of math. modeling in predicting treatment responses. Finally, we provide insights on and perspectives for future development of effective therapeutic ROS-inducing anticancer agents or antioxidants for cancer treatment.
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    McIlwain, D. R.; Berger, T.; Mak, T. W. Caspase Functions in Cell Death and Disease. Cold Spring Harbor Perspect. Biol. 2013, 5, a008656  DOI: 10.1101/cshperspect.a008656
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    Caspase functions in cell death and disease
    McIlwain, David R.; Berger, Thorsten; Mak, Tak W.
    Cold Spring Harbor Perspectives in Biology (2013), 5 (4), a008656/1-a008656/28CODEN: CSHPEU; ISSN:1943-0264. (Cold Spring Harbor Laboratory Press)
    A review. Caspases are a family of endoproteases that provide crit. links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their prodn. as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromol. complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the prodn. of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.
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    Roy, S.; Bhattacharya, K.; Mandal, C.; Dasgupta, A. K. Cellular Response to Chirality and Amplified Chirality. J. Mater. Chem. B 2013, 1, 6634– 6643,  DOI: 10.1039/c3tb21322f
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    Cellular response to chirality and amplified chirality
    Roy, Sarita; Bhattacharya, Kaushik; Mandal, Chitra; Dasgupta, Anjan Kr.
    Journal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (48), 6634-6643CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
    In this paper we have explored how cancer cell line U87MG responds to drug penicillamine (PA) with reciprocal enantiomeric identities (i.e.l, d-forms). As nano-conjugation leads to amplification of chirality, cellular response to resp. chiral forms is studied in the presence and absence of nano-conjugation. The L,D-forms of the drug (penicillamine) and their silver nanoparticle conjugated forms are used and characterized by CD and fourier transform IR spectroscopy. The authors report that cells discriminate between the chiral forms through various mechanisms e.g. by altering mitochondrial membrane potential and selected elements of the caspase pathway. The striking feature which the authors would like to report is that chirality and the amplified chirality induced reciprocal responses may be dissimilar and even reciprocal. The work shows that the cellular response to geometrical chirality is an evolved concept and an amplified chirality by processes like nano-conjugation may be translated into an altered message in the cell.
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    Bhattacharya, K.; Samanta, S. K.; Tripathi, R.; Mallick, A.; Chandra, S.; Pal, B. C.; Shaha, C.; Mandal, C. Apoptotic Effects of Mahanine on Human Leukemic Cells are Mediated Through Crosstalk Between Apo-1/Fas Signaling and the Bid Protein and via Mitochondrial Pathways. Biochem. Pharmacol. 2010, 79, 361– 372,  DOI: 10.1016/j.bcp.2009.09.007
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    Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways
    Bhattacharya, Kaushik; Samanta, Suman K.; Tripathi, Rakshamani; Mallick, Asish; Chandra, Sarmila; Pal, Bikas C.; Shaha, Chandrima; Mandal, Chitra
    Biochemical Pharmacology (2010), 79 (3), 361-372CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
    Apo-1 (Fas/CD95), a cell surface receptor, triggers apoptosis after binding to its physiol. ligand, Apo-1L (FasL/CD95L). This study reports that mahanine, purified from the leaves of Murraya koenigii, has a dose- and time-dependent anti-proliferative activity in acute lymphoid (MOLT-3) and chronic myeloid (K562) leukemic cell lines and in the primary cells of leukemic and myeloid patients, with minimal effect on normal immune cells including CD34+ cells. Leukemic cells underwent phosphatidylserine externalization and DNA fragmentation, indicating mahanine-induced apoptosis. An increase in reactive oxygen species suggests that the mahanine-induced apoptosis was mediated by oxidative stress. A significant drop in the Bcl2/Bax ratio, the loss of mitochondrial transmembrane potential as well as cytochrome c release from the mitochondria to the cytosol suggested involvement of the mitochondrial pathway of apoptosis. Cytochrome c release was followed by the activation of caspase-9, caspase-3 and caspase-7, and cleavage of PARP in both MOLT-3 and K562 cells. In MOLT-3 cells, formation of the Fas-FasL-FADD-caspase-8 heterotetramer occurred, leading to the cleavage of Bid to its truncated form, which consequently resulted in formation of the mitochondrial transmembrane pore. The incubation of MOLT-3 cells with mahanine in the presence of caspase-8 inhibitor or FasL-neutralizing NOK-2 antibody resulted in the decrease of mahanine-induced cell death. Mahanine was also a potent inhibitor of K562 xenograft growth, which was evident in an athymic nude mice model. In summary, these results provide evidence for involvement of the death receptor-mediated extrinsic pathway of apoptosis in the mahanine-induced anticancer activity in MOLT-3 cells, but not in K562 cells, which are deficient in Fas/FasL.
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    Echeverria, P. C.; Bhattacharya, K.; Joshi, A.; Wang, T.; Picard, D. The Sensitivity to Hsp90 Inhibitors of Both Normal and Oncogenically Transformed Cells is Determined by the Equilibrium Between Cellular Quiescence and Activity. PLoS One 2019, 14, e0208287  DOI: 10.1371/journal.pone.0208287
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    The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
    Echeverria, Pablo C.; Bhattacharya, Kaushik; Joshi, Abhinav; Wang, Tai; Picard, Didier
    PLoS One (2019), 14 (2), e0208287CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The mol. chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large no. of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clin. trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal vs. cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic anal. of the impact of three chem. different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metab. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.
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    Lanzetti, L.; Di Fiore, P. P. Endocytosis and Cancer: an ‘Insider’ Network with Dangerous Liaisons. Traffic 2008, 9, 2011– 2021,  DOI: 10.1111/j.1600-0854.2008.00816.x
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    Endocytosis and cancer: an 'insider' network with dangerous liaisons
    Lanzetti, Letizia; Di Fiore, Pier Paolo
    Traffic (Oxford, United Kingdom) (2008), 9 (12), 2011-2021CODEN: TRAFFA; ISSN:1398-9219. (Wiley-Blackwell)
    A review. From the signaling point of view, endocytosis has long been regarded as a major mechanism of attenuation, through the degrdn. of signaling receptors and, in some cases, of their ligands. This outlook has changed, over the past decade, as it has become clear that signaling persists in the endocytic route, and that intracellular endocytic stations (the 'signaling endosomes') actually contribute to the sorting of signals in space and time. Endocytosis-mediated recycling of receptors and of signaling mols. to specific regions of the plasma membrane is also coming into focus as a major mechanism in the execution of spatially restricted functions, such as cell motility. In addn., emerging evidence connects endocytosis as a whole, or individual endocytic proteins, to complex cellular programs, such as the control of the cell cycle, mitosis, apoptosis and cell fate detn. Thus, endocytosis seems to be deeply ingrained into the cell regulation blueprint and its subversion is predicted to play an important role in human diseases: first and foremost, cancer.
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    Faklaris, O.; Joshi, V.; Irinopoulou, T.; Tauc, P.; Sennour, M.; Girard, H.; Gesset, C.; Arnault, J.-C.; Thorel, A.; Boudou, J.-P.; Curmi, P. A.; Treussart, F. Photoluminescent Diamond Nanoparticles for Cell Labeling: Study of the Uptake Mechanism in Mammalian Cells. ACS Nano 2009, 3, 3955– 3962,  DOI: 10.1021/nn901014j
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    Photoluminescent Diamond Nanoparticles for Cell Labeling: Study of the Uptake Mechanism in Mammalian Cells
    Faklaris, Orestis; Joshi, Vandana; Irinopoulou, Theano; Tauc, Patrick; Sennour, Mohamed; Girard, Hugues; Gesset, Celine; Arnault, Jean-Charles; Thorel, Alain; Boudou, Jean-Paul; Curmi, Patrick A.; Treussart, Francois
    ACS Nano (2009), 3 (12), 3955-3962CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Diamond nanoparticles (nanodiamonds) have been recently proposed as new labels for cellular imaging. For small nanodiamonds (size <40 nm), resonant laser scattering and Raman scattering cross sections are too small to allow single nanoparticle observation. Nanodiamonds can, however, be rendered photoluminescent with a perfect photostability at room temp. Such a remarkable property allows easier single-particle tracking over long time scales. In this work, the authors use photoluminescent nanodiamonds of size <50 nm for intracellular labeling and investigate the mechanism of their uptake by living cells. By blocking selectively different uptake processes, the authors show that nanodiamonds enter cells mainly by endocytosis, and converging data indicate that it is clathrin-mediated. The authors also examine nanodiamond intracellular localization in endocytic vesicles using immunofluorescence and TEM. The authors find a high degree of colocalization between vesicles and the biggest nanoparticles or aggregates, while the smallest particles appear free in the cytosol. The authors' results pave the way for the use of photoluminescent nanodiamonds in targeted intracellular labeling or biomol. delivery.
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    Jiang, X.; Röcker, C.; Hafner, M.; Brandholt, S.; Dörlich, R. M.; Nienhaus, G. U. Endo- and Exocytosis of Zwitterionic Quantum Dot Nanoparticles by Live HeLa Cells. ACS Nano 2010, 4, 6787– 6797,  DOI: 10.1021/nn101277w
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    Endo- and Exocytosis of Zwitterionic Quantum Dot Nanoparticles by Live HeLa Cells
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    ACS Nano (2010), 4 (11), 6787-6797CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Uptake and intracellular transport of D-penicillamine coated quantum dots (DPA-QDs) of 4 nm radius by live HeLa cells have been investigated systematically by spinning disk and 4Pi confocal microscopies. Unlike larger nanoparticles, these small DPA-QDs were obsd. to accumulate at the plasma membrane prior to internalization, and the uptake efficiency scaled nonlinearly with the nanoparticle concn. Both observations indicate that a crit. threshold d. has to be exceeded for triggering the internalization process. By using specific inhibitors, we showed that DPA-QDs were predominantly internalized by clathrin-mediated endocytosis and to a smaller extent by macropinocytosis. Clusters of DPA-QDs were found in endosomes, which were actively transported along microtubules toward the perinuclear region. Later on, a significant fraction of endocytosed DPA-QDs were found in lysosomes, while others were actively transported to the cell periphery and exocytosed with a half-life of 21 min.
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    Zhao, J.; Stenzel, M. H. Entry of Nanoparticles into Cells: The Importance of Nanoparticle Properties. Polym. Chem. 2018, 9, 259– 272,  DOI: 10.1039/C7PY01603D
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    Knowledge of the interactions between nanoparticles (NPs) and cell membranes is of great importance for the design of safe and efficient nanomedicines. Extensive studies aimed at understanding the correlation of NP properties with endocytosis have been carried out in the past few years. Here, we review the recent progress of these studies and provide an overview of the current state of knowledge on the influence of NP size, shape, stiffness and surface chem. on cellular uptake. Special attention was dedicated to the uptake of non-spherical nanoparticles. Some general principles obtained from these fundamental studies will serve as guidelines for the design of optimized NP for enhanced cellular uptake. Finally, the opportunities for polymer chemists are discussed.
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    Clathrin-mediated endocytosis is inhibited during mitosis
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    Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (17), 6572-6577, S6572/1-S6572/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    A long-standing paradigm in cell biol. is the shutdown of endocytosis during mitosis. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase. A recent study proposed that endocytosis is continuous throughout the cell cycle and that the obsd. inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, and not to a shutdown of endocytosis. This challenge to the established view is gradually becoming accepted. Because of this controversy, we revisited the question of endocytic activity during mitosis. Using an antibody uptake assay and controlling for potential changes in surface receptor d., we demonstrate the strong inhibition of endocytosis in mitosis of CD8 chimeras contg. any of the three major internalization motifs for clathrin-mediated endocytosis (YXXΦ, [DE]XXXL[LI], or FXNPXY) or a CD8 protein with the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. The shutdown is not gradual: We describe a binary switch from endocytosis being "on" in interphase to "off" in mitosis as cells traverse the G2/M checkpoint. In addn., we show that the inhibition of transferrin uptake in mitosis occurs despite abundant transferrin receptor at the surface of HeLa cells. Our study finds no support for the recent idea that endocytosis continues during mitosis, and we conclude that endocytosis is temporarily shutdown during early mitosis.
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    Endocytosis Resumes during Late Mitosis and Is Required for Cytokinesis
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    Recent work has underscored the importance of membrane trafficking events during cytokinesis. For example, targeted membrane secretion occurs at the cleavage furrow in animal cells, and proteins that regulate endocytosis also influence the process of cytokinesis. Nonetheless, the prevailing dogma is that endosomal membrane trafficking ceases during mitosis and resumes after cell division is complete. In this study, we have characterized endocytic membrane trafficking events that occur during mammalian cell cytokinesis. We have found that, although endocytosis ceases during the early stages of mitosis, it resumes during late mitosis in a temporally and spatially regulated pattern as cells progress from anaphase to cytokinesis. Using fixed and live cell imaging, we have found that, during cleavage furrow ingression, vesicles are internalized from the polar region and subsequently trafficked to the midbody area during later stages of cytokinesis. In addn., we have demonstrated that cytokinesis is inhibited when clathrin-mediated endocytosis is blocked using a series of dominant neg. mutants. In contrast to previous thought, we conclude that endocytosis resumes during the later stages of mitosis, before cytokinesis is completed. Furthermore, based on our findings, we propose that the proper regulation of endosomal membrane traffic is necessary for the successful completion of cytokinesis.
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    Zheng, K.; Xie, J. Engineering Ultrasmall Metal Nanoclusters as Promising Theranostic Agents. Trends Chem. 2020, 2, 665– 679,  DOI: 10.1016/j.trechm.2020.04.011
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    A review. Metal nanoclusters (NCs) are ultrasmall nanoparticles with intriguing mol.-like physicochem. properties. In recent years, metal NCs have been used as theranostic agents in biomedicine. In this short review, we correlate the physicochem. properties of metal NCs to their biomedical applications, shedding some light on the design of metal NC-based theranostic agents in cancer therapy, imaging-guided therapy, antimicrobial agents, and bioimaging. Such design principles could be readily realized in atomically precise metal NCs, leveraging recent advances in synthetic chem. and the structural resoln. of metal NCs.
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    Dejonghe, W.; Kuenen, S.; Mylle, E.; Vasileva, M.; Keech, O.; Viotti, C.; Swerts, J.; Fendrych, M.; Ortiz-Morea, F. A.; Mishev, K.; Delang, S.; Scholl, S.; Zarza, X.; Heilmann, M.; Kourelis, J.; Kasprowicz, J.; Nguyen, L. S. L.; Drozdzecki, A.; Van Houtte, I.; Szatmári, A.-M.; Majda, M.; Baisa, G.; Bednarek, S. Y.; Robert, S.; Audenaert, D.; Testerink, C.; Munnik, T.; Van Damme, D.; Heilmann, I.; Schumacher, K.; Winne, J.; Friml, J.; Verstreken, P.; Russinova, E. Mitochondrial Uncouplers Inhibit Clathrin-Mediated Endocytosis Largely Through Cytoplasmic Acidification. Nat. Commun. 2016, 7, 11710,  DOI: 10.1038/ncomms11710
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    Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (Kd = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.
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  2. Vikas Tiwari, Sonali Garg, Tarak Karmakar. Insights into the Interactions of Peptides with Monolayer-Protected Metal Nanoclusters. ACS Applied Bio Materials 2023, Article ASAP.
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  5. Youkun Zheng, Yuxin Zhu, Jianghong Dai, Jiaojiao Lei, Jingcan You, Ni Chen, Liqun Wang, Mao Luo, Jianbo Wu. Atomically precise Au nanocluster-embedded carrageenan for single near-infrared light-triggered photothermal and photodynamic antibacterial therapy. International Journal of Biological Macromolecules 2023, 230 , 123452. https://doi.org/10.1016/j.ijbiomac.2023.123452
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  • Abstract

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    Figure 1

    Figure 1. Characterization of CNC and GNC. (a) The top image shows the structure of the Au25(SR)18 nanocluster (color code: Au atoms, dark yellow; S atoms, green); the ligands (Capt or GSH) are omitted for clarity. The bottom image shows the structure of captopril (Capt) and glutathione (GSH) ligands used for the synthesis of CNC (Au25(Capt)18) and GNC (Au25(GSH)18). (b) UV–vis spectra of the synthesized CNC (red dotted line) and GNC (green squared line). The inset of the figure represents the color of the synthesized CNC and GNC in an aqueous solution. (c) The MALDI mass spectrum of CNC (Au25(Capt)18) recorded in positive mode with α-CHCA as the matrix. The peak marked with an asterisk (*) corresponds to the most important fragment Au21(Capt)14. (d) The ESI spectrum of GNC (Au25(GSH)18) gives characteristic peaks at m/z 809 and 1005 due to [Au(SG)2-H]−1 and [Au2(SG)2-H]−1, respectively. (e) The upper and lower panels, respectively, represent the morphology and size distributions of CNC and GNC obtained by TEM.

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    Figure 2

    Figure 2. Cytotoxicity of nanoclusters and ligands on cancer cells. (a) Effects of CNC and GNC (0–500 μg/mL) and the corresponding ligands (Capt and GSH, respectively) on cell viability measured by the CTG assay in HEK293T cells after 72 h treatment (n = 3 biologically independent samples). (b) Only CNC induces a higher percentage of cell death in HEK293T cells as determined by the PI staining assay measured by flow cytometry, whereas GNC and the corresponding ligands (Capt and GSH) are neutral (n = 4 biologically independent samples). Membrane ruptured cells can only be visualized by PI staining and designated as the ″dead cell″ population. (c) The left panel represents the apoptotic cell percentage calculated by the flow-cytometry-based cell cycle assay. Only CNC induces significant apoptosis. The right panel shows that CNC arrests HEK293T cells in the G2/M phase of the cell cycle (n = 3 biologically independent samples). For the bar graphs, the data are represented as mean values ± SEM (standard error of the mean).

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    Figure 3

    Figure 3. Energy-dependent CME drives CNC internalization. (a) Dual-color confocal images of HeLa cells labeled with CNC (red color) and exogenously expressed intracellular EGFP (green color). The first row represents HeLa cells without transfection with the EGFP expression plasmid pEGFP-C1. The second and third rows represent cells stained with either CNC or cells transiently transfected with pEGFP-C1. The last row represents the transfected Hela cells with pEGFP-C1 and treated with CNC. The merging of the DIC (differential interference contrast) channel and the other two channels (red: CNC and green: EGFP channel) indicates the colocalization of CNC with EGFP as evident by the yellow color (n = at least 3 independent experiments). It must be noted that these transfection assays with pEGFP-C1 are transient transfections. Scale bar represents 10 μm. (b) The effect of temperature on CNC uptake by HeLa cells. Confocal microscopy of HeLa cells treated with CNC grown in two different temperatures: 4 and 37 °C (n = 2 independent biological samples). Scale bar represents 10 μm. (c) Bar graph representing the mean fluorescence intensity in arbitrary unit (a.u.) showing a comparison of CNC uptake at two different temperatures compared to control (n = a minimum of 50 cells was considered for calculating the mean fluorescence intensity, MFI). (d) Confocal images of HeLa cells pretreated with different endocytosis inhibitors and further incubated with CNC for 8 h to evaluate the uptake efficiency (n = 2 independent biological samples). Scale bar represents 10 μm. (e) Bar graph of mean fluorescence intensity (a.u.) relative to the control sample showing the effect of different inhibitors of the endocytic pathway on the uptake of CNC (n = a minimum of 50 cells was taken into account for calculating the MFI of a particular set). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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    Figure 4

    Figure 4. CNC inhibits complex V of mitochondrial ETC. (a) OCR and (b) ECAR of HeLa cells were monitored using the Seahorse Bioscience Extra Cellular Flux Analyzer in real time. The first few minutes (∼20 min) represent the basal OCR or ECAR of HeLa cells followed by the injection of nanoclusters and then the sequential addition of the ATP synthase inhibitor (oligomycin 5 μM), FCCP (1 μM), and a mixture of rotenone (1 μM) and antimycin (1 μM) was performed. OCR is an indicator of mitochondrial respiration, and ECAR is predominately a measure of glycolytic flux. (c) OCR and (d) ECAR of HeLa cells pretreated with either CNC or GNC for different times (1, 2, and 4 h) and effect of mitochondrial inhibitors in the same order (oligomycin, FCCP, and rotenone + antimycin). (e) OCR and (f) ECAR of Hela cells pretreated with either CNC or GNC for different times (1, 2, and 4 h). Note that the order of addition of the inhibitors was changed. Here, pretreated cells were first treated with the antimycin A and rotenone mixture and subsequently with FCCP and oligomycin A. All data are reported as means ± SD (n = 3 experimental sets). (g) ATP production rates are calculated from the data presented in panel c for HeLa cells pretreated with CNC and GNC. The ATP production rate is calculated as (last OCR measurement before oligomycin injection) – (OCR rate measured after oligomycin injection). All data are presented as means ± SEM (n = minimum of 3 independent biological samples). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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    Figure 5

    Figure 5. CNC-induced mitochondrial respiratory dysfunction triggers intracellular ROS and apoptosis. (a) Intracellular ROS levels were measured by flow cytometry using the H2DCFDA staining assay in HeLa cells treated with CNC, GNC, and their corresponding ligands. For the line graphs, the data are represented as mean values ± SEM (n = 4 biologically independent samples). (b) Mitochondrial ROS levels were measured in HeLa cells after treatment with CNC (500 μg/mL) using MitoSox staining (n = 4 biologically independent samples). (c) Bar graph representing the percentage of mitochondrial membrane depolarized cells as a function of time (0, 3, 6, 12, 24, and 36 h) upon CNC (500 μg/mL) treatment (n = 4 biologically independent samples). (d) Confocal images of HeLa cells transiently transfected with mitochondrially targeted EGFP (mitoEGFP) and later treated with CNC to study the colocalization of CNC into mitochondria. The first row represents HeLa cells without transfection with mitoEGFP. The second and third rows represent cells either stained with CNC or transiently transfected with mitoEGFP. The last row represents HeLa cells transiently transfected with mitoEGFP and then treated with CNC to study the colocalization of CNC into mitochondria. The yellow color in the merged image confirms the localization of CNC in mitochondria. It has to be noted that these transfection assays with pEGFP-C1 are transient transfections. (e) Western blot analysis of Hela cells after treating them with different concentrations of CNC and GNC (200, 300, 400, and 500 μg/mL). The analysis indicates that CNC strikingly reduces the pro-form of caspase 9. α-Tubulin served as a loading control.

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    Figure 6

    Figure 6. Restriction in the internalization of CNC protects cells from cell cycle arrest and reduced viability. (a) A comparison of intracellular ROS levels measured in Hela cells treated with CNC (500 μg/mL, red line) and HeLa cells pretreated with endocytic inhibitors Pitstop 2 (40 μM, blue line) and Dynasore (80 μM) to block the uptake of CNC inside the cells. (b) Cell cycle analysis revealed that pretreatment of Pitstop 2 (40 μM) on Hela cells partially protects from CNC (500 μg/mL)-induced G2/M phase cell cycle arrest. (c) A significantly higher number of viable cells were found in the case of HeLa cells pretreated with Pitstop 2 (40 μM) followed by CNC treatment compared to cells treated with only CNC. (d) Cell cycle analysis revealed that vitamin C (75 μM) pretreatment on Hela cells partially protects them from CNC-induced G2/M phase cell cycle arrest. (e) A significantly higher number of viable cells were found in the case of HeLa cells pretreated with vitamin C (75 μM) followed by CNC treatment compared to cells treated with only CNC. The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests.

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    Figure 7

    Figure 7. Oncogenic transformation renders cells vulnerable to CNC-induced death. (a) Comparative OCR profiles of HFs (normal parental), HFs-hTERT (normal immortalized), and HFs-hTERT + SV40 + Ras G12V (oncogenically transformed) and effects of mitochondrial inhibitors (oligomycin, FCCP, and rotenone + antimycin) on them (n = 5 biologically independent samples). (b) Bar graphs represent the comparative basal OCR (left; first ∼20 min of respiration), rate of ATP production [middle; ATP production is calculated as (last OCR measurement before oligomycin injection) – (OCR rate measured after oligomycin injection)], and maximal respiratory rate [right; maximal respiratory rate is calculated as (last OCR measurement after oligomycin injection) – (OCR rate measured after FCCP injection)] of HFs (normal parental), HFs-hTERT (normal immortalized), and HFs-hTERT + SV40 + Ras G12V (cancer) cells. All these calculations were done on the experiment presented in panel a. (c) Measurements of total cellular ROS by H2DCFDA staining in the indicated cells in the presence and absence of CNC (n = 3 biologically independent samples). (d) Comparison of cell viability of the indicated cells after 5 days of treatment with CNC (n = 2 biologically independent samples). Note that, in this experiment, we seeded 6 × 103 cells. (e) Measurements of apoptotic cells (<2n nucleus in cell cycle analysis) after 48 h of treatment with CNC of the indicated cells (n = 2 biologically independent samples). The statistical significance between the groups was analyzed by two-tailed unpaired Student’s t tests. *p < 0.05, **p < 0.01.

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    This article references 73 other publications.

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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlyiurbE&md5=78b9f295abe01abe248e49a935981c0f
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      Zheng, Y.; Lai, L.; Liu, W.; Jiang, H.; Wang, X. Recent advances in biomedical applications of fluorescent gold nanoclusters. Adv. Colloid Interface Sci. 2017, 242, 1– 16,  DOI: 10.1016/j.cis.2017.02.005
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      10
      Recent advances in biomedical applications of fluorescent gold nanoclusters
      Zheng, Youkun; Lai, Lanmei; Liu, Weiwei; Jiang, Hui; Wang, Xuemei
      Advances in Colloid and Interface Science (2017), 242 (), 1-16CODEN: ACISB9; ISSN:0001-8686. (Elsevier B.V.)
      A review. Fluorescent gold nanoclusters (AuNCs) are emerging as novel fluorescent materials and have attracted more and more attention in the field of biolabeling, biosensing, bioimaging and targeted cancer treatment because of their unusual physicochem. properties, such as long fluorescence lifetime, ultrasmall size, large Stokes shift, strong photoluminescence, as well as excellent biocompatibility and photostability. Recently, significant efforts have been committed to the prepn., functionalization and biomedical application studies of fluorescent AuNCs. In this review, we have summarized the strategies for prepn. and surface functionalization of fluorescent AuNCs in the past several years, and highlighted recent advances in the biomedical applications of the relevant fluorescent AuNCs. Based on these observations, we also give a discussion on the current problems and future developments of the fluorescent AuNCs for biomedical applications.
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    11. 11
      Zheng, Y.; Wu, J.; Jiang, H.; Wang, X. Gold nanoclusters for theranostic applications. Coord. Chem. Rev. 2021, 431, 213689  DOI: 10.1016/j.ccr.2020.213689
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      11
      Gold nanoclusters for theranostic applications
      Zheng, Youkun; Wu, Jianbo; Jiang, Hui; Wang, Xuemei
      Coordination Chemistry Reviews (2021), 431 (), 213689CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      A review. Gold nanoclusters, consisting of a few to several hundred Au atoms with a core size below 2 nm, have attracted worldwide attention in the biomedicine because of their supernormal physicochem. properties and excellent biocompatibility. In recent years, significant efforts have been devoted to the development of gold nanoclusters for diagnostic and therapeutic applications. In this review, we focus on the research progress and new prospects in this field, and introduce the burgeoning advances on the utilization of gold nanoclusters for disease-related diagnostic (involving biol. anal., and biol. imaging), and therapeutic applications. Based on these efforts, we also discussed the future development of functionalized gold nanoclusters for theranostic applications. With the deepening of research, we expect versatile gold nanoclusters to become an essential platform for biomedical applications.
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    12. 12
      Shang, L.; Dörlich, R. M.; Brandholt, S.; Schneider, R.; Trouillet, V.; Bruns, M.; Gerthsen, D.; Nienhaus, G. U. Facile Preparation of Water-Soluble Fluorescent Gold Nanoclusters for Cellular Imaging Applications. Nanoscale 2011, 3, 2009– 2014,  DOI: 10.1039/c0nr00947d
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      12
      Facile preparation of water-soluble fluorescent gold nanoclusters for cellular imaging applications
      Shang, Li; Doerlich, Rene M.; Brandholt, Stefan; Schneider, Reinhard; Trouillet, Vanessa; Bruns, Michael; Gerthsen, Dagmar; Nienhaus, G. Ulrich
      Nanoscale (2011), 3 (5), 2009-2014CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      We report a facile strategy to synthesize water-sol., fluorescent gold nanoclusters (AuNCs) in one step by using a mild reductant, tetrakis(hydroxymethyl)phosphonium chloride (THPC). A zwitterionic functional ligand, D-penicillamine (DPA), as a capping agent endowed the AuNCs with excellent stability in aq. solvent over the physiol. relevant pH range. The DPA-capped AuNCs displayed excitation and emission bands at 400 and 610 nm, resp.; the fluorescence quantum yield was 1.3%. The effect of borohydride redn. on the optical spectra and XPS results indicated that the AuNC luminescence is closely related to the presence of Au(I) on their surfaces. In a first optical imaging application, we studied internalization of the AuNCs by live HeLa cells using confocal microscopy with two-photon excitation. A cell viability assay revealed good biocompatibility of these AuNCs. Our studies demonstrate a great potential of DPA-stabilized AuNCs as fluorescent nanoprobes in bioimaging and related applications.
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    13. 13
      Zheng, K.; Setyawati, M. I.; Leong, D. T.; Xie, J. Antimicrobial Gold Nanoclusters. ACS Nano 2017, 11, 6904– 6910,  DOI: 10.1021/acsnano.7b02035
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      13
      Antimicrobial Gold Nanoclusters
      Zheng, Kaiyuan; Setyawati, Magdiel I.; Leong, David Tai; Xie, Jianping
      ACS Nano (2017), 11 (7), 6904-6910CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Bulk gold (Au) is known to be chem. inactive. However, when the size of Au nanoparticles (Au NPs) decreases to close to 1 nm or sub-nanometer dimensions, these ultrasmall Au nanoclusters (Au NCs) begin to possess interesting phys. and chem. properties and likewise spawn different applications when working with bulk Au or even Au NPs. In this study, we found that it is possible to confer antimicrobial activity to Au NPs through precise control of their size down to NC dimension (typically less than 2 nm). Au NCs could kill both Gram-pos. and Gram-neg. bacteria. This wide-spectrum antimicrobial activity is attributed to the ultrasmall size of Au NCs, which would allow them to better interact with bacteria. The interaction between ultrasmall Au NCs and bacteria could induce a metabolic imbalance in bacterial cells after the internalization of Au NCs, leading to an increase of intracellular reactive oxygen species prodn. that kills bacteria consequently.
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    14. 14
      Qi, J.; Liu, Y.; Xu, H.; Xue, T.; Su, Y.; Lin, Z. Anti-Cancer Effect of Melittin-Au25(MHA)18 Complexes on Human Cervical Cancer HeLa Cells. J. Drug Delivery Sci. Technol. 2022, 68, 103078  DOI: 10.1016/j.jddst.2021.103078
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      14
      Anti-cancer effect of melittin-Au25(MHA)18 complexes on human cervical cancer HeLa cells
      Qi, Jinxia; Liu, Yuxin; Xu, Hejie; Xue, Tiantian; Su, Yu; Lin, Zhenkun
      Journal of Drug Delivery Science and Technology (2022), 68 (), 103078CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)
      Melittin (MEL) is the major component of bee venom, which has recently emerged as an attractive candidate for cancer chemotherapy. As a polypeptide, rapid degrdn. of MEL is considered as one of the most crit. challenges in therapeutic applications. In this study, atomically precise gold nanoclusters with 6-mercaptohexanoic acid (MHA) as a thiolate ligand, termed as Au25(MHA)18, were synthesized and employed as the delivery vehicles of MEL to human cervical cancer HeLa cells. The characterization including Zeta potential, UV-Vis spectra, XPS, and transmission electron microscope (TEM), showed that Au25(MHA)18 nanoclusters can load MEL with high efficiency, resulting in formation of MEL-Au25(MHA)18 complexes. The anti-cancer effect of MEL-Au25(MHA)18 complexes on human cervical cancer HeLa cells in vitro were further evaluated by cell proliferation and cytotoxicity assay, flow cytometry assay, and confocal microscopy imaging. It was found that Au25(MHA)18 nanoclusters protected MEL from degrdn. leading to long-lasting cytotoxicity on HeLa cells, and maintained the good anti-cancer activity of MEL. The anti-cancer activity of MEL-Au25(MHA)18 complexes on HeLa cells can be well explained through the pore formation by MEL on the surface of cell membrane, which ultimately leading to cytolysis. This work demonstrated the feasibility of atomically precise gold nanoclusters as the delivery vehicles of unstable polypeptide such as MEL, achieving improved efficiency in chemotherapy.
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    15. 15
      Srinivasulu, Y. G.; Mozhi, A.; Goswami, N.; Yao, Q.; Xie, J. Gold Nanocluster Based Nanocomposites for Combinatorial Antibacterial Therapy for Eradicating Biofilm Forming Pathogens. Mater. Chem. Front. 2022, 6, 689– 706,  DOI: 10.1039/D1QM00936B
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      There is no corresponding record for this reference.
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      McLean, A.; Wang, R.; Huo, Y.; Cooke, A.; Hopkins, T.; Potter, N.; Li, Q.; Isaac, J.; Haidar, J.; Jin, R.; Kopelman, R. Synthesis and Optical Properties of Two-Photon-Absorbing Au25(Captopril)18-Embedded Polyacrylamide Nanoparticles for Cancer Therapy. ACS Appl. Nano Mater. 2020, 3, 1420– 1430,  DOI: 10.1021/acsanm.9b02272
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      16
      Synthesis and Optical Properties of Two-Photon-Absorbing Au25(Captopril)18-Embedded Polyacrylamide Nanoparticles for Cancer Therapy
      McLean, Alan; Wang, Ruofei; Huo, Ying; Cooke, Alexander; Hopkins, Thomas; Potter, Natalie; Li, Qi; Isaac, Joseph; Haidar, Jalal; Jin, Rongchao; Kopelman, Raoul
      ACS Applied Nano Materials (2020), 3 (2), 1420-1430CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      Au25(Captopril)18 nanoclusters (NCs) are a 1.2 nm water-sol. metal nanomaterial with strong two-photon absorption, with excited-state reactive oxygen prodn., and of potential applicability for biomedical imaging and two-photon photodynamic therapy (2p-PDT). Because of the low cellular uptake of Au25(Captopril)18 clusters, its limited potential for conjugation with targeting agents, and to enhance its biocompatibility, we embedded these clusters into hydrogel nanoparticles (NPs) by synthesizing polyacrylamide-encapsulated Au25(Capt)18 nanoparticles (PAAm-Au25(Capt)18 NPs). We verified that the two-photon absorption and singlet oxygen prodn. of these PAAm-Au25 NPs still exhibit the favorable properties of the original metal nanocluster. Furthermore, the Au25-encapsulated polyacrylamide nanoparticles have enhanced in vitro cell uptake, can be easily conjugated to targeting moieties, and exhibit significantly higher biocompatibility. Photoirradn. expts. on HeLa cancer cells incubated with these PAAm-Au25(Capt)18 NPs reveal excellent 2p-PDT efficacy, in contrast to 1p-PDT, thus demonstrating their promising potential for cancer PDT with IR light that penetrates deeply into live tissue.
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    17. 17
      Carlos-Escalante, J. A.; de Jesús-Sánchez, M.; Rivas-Castro, A.; Pichardo-Rojas, P. S.; Arce, C.; Wegman-Ostrosky, T. The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer. Front. Oncol. 2021, 11, 660943  DOI: 10.3389/fonc.2021.660943
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      17
      The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer
      Carlos-Escalante Jose A; de Jesus-Sanchez Marcela; Rivas-Castro Alejandro; Pichardo-Rojas Pavel S; Arce Claudia; Wegman-Ostrosky Talia
      Frontiers in oncology (2021), 11 (), 660943 ISSN:2234-943X.
      Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.
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    18. 18
      Kennedy, L.; Sandhu, J. K.; Harper, M.-E.; Cuperlovic-Culf, M. Role of Glutathione in Cancer: From Mechanisms to Therapies. Biomolecules 2020, 10, 1429,  DOI: 10.3390/biom10101429
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      18
      Role of glutathione in cancer: from mechanisms to therapies
      Kennedy, Luke; Sandhu, Jagdeep K.; Harper, Mary-Ellen; Cuperlovic-Culf, Miroslava
      Biomolecules (2020), 10 (10), 1429CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      A review. Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concns. in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Mol. changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are assocd. with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.
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    19. 19
      Katla, S. K.; Zhang, J.; Castro, E.; Bernal, R. A.; Li, X. Atomically Precise Au25(SG)18 Nanoclusters: Rapid Single-Step Synthesis and Application in Photothermal Therapy. ACS Appl. Mater. Interfaces 2018, 10, 75– 82,  DOI: 10.1021/acsami.7b12614
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      19
      Atomically Precise Au25(SG)18 Nanoclusters: Rapid Single-Step Synthesis and Application in Photothermal Therapy
      Katla, Sai Krishna; Zhang, Jie; Castro, Edison; Bernal, Ricardo A.; Li, XiuJun
      ACS Applied Materials & Interfaces (2018), 10 (1), 75-82CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Remarkable recent advances on Au25(SR)18 nanoclusters have led to significant applications in catalysis, sensing, and magnetism. However, the existing synthetic routes are complicated, particularly for the water-sol. Au25(SG)18 nanoclusters. Here, we report a single-step concn. and temp.-controlled method for rapid synthesis of the Au25(SG)18 nanoclusters in as little as 2 h without the need for low-temp. reaction or even stirring. A systematic time-based investigation was carried out to study the effects of vol., concn., and temp. on the synthesis of these nanoclusters. Further, we discovered for the first time that the Au25(SG)18 nanoclusters exhibit excellent photothermal activities in achieving 100% cell death for MDA-MB-231 breast cancer cells at a power of 10 W/cm2 using an 808 nm laser source, demonstrating applications toward photothermal therapy.
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    20. 20
      Roy Bhattacharya, S.; Bürgi, T. Amplified Vibrational Circular Dichroism as a Manifestation of the Interaction Between a Water Soluble Gold Nanocluster and Cobalt Salt. Nanoscale 2019, 11, 23226– 23233,  DOI: 10.1039/C9NR07534H
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      20
      Amplified vibrational circular dichroism as a manifestation of the interaction between a water soluble gold nanocluster and cobalt salt
      Roy Bhattacharya, Sarita; Burgi, Thomas
      Nanoscale (2019), 11 (48), 23226-23233CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Vibrational CD (VCD) is a powerful tool for the structure detn. of dissolved mols. However, the application of VCD to nanostructures is limited up to now due to the weakness of the effect and hence the low signal intensities. Here we show that the addn. of a small amt. of cobalt(II) drastically enhances the VCD signals of a thiolate-protected gold cluster Au25(Capt)18 (Capt = captopril) in aq. soln. An increase of VCD signal intensity of at least one order of magnitude is obsd. The enhancement depends on the amt. of CoCl2 added but almost an order of magnitude enhancement is already obsd. at a cluster : CoCl2 ratio of 1 : 1. In contrast, CD (CD) and IR spectra hardly change. The increase in VCD intensity goes along with a qual. change of the spectrum and the enhancement increases with time reaching a stable state only after several hours. The enhancement is due to an interaction between the cobalt(II) and the cluster, which also leads to quenching of its fluorescence. The behavior is completely different for free captopril, where the addn. of cobalt(II) salt does not affect the VCD spectrum.
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    21. 21
      Hahn, W. C.; Counter, C. M.; Lundberg, A. S.; Beijersbergen, R. L.; Brooks, M. W.; Weinberg, R. A. Creation of Human Tumour Cells with Defined Genetic Elements. Nature 1999, 400, 464– 468,  DOI: 10.1038/22780
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      Creation of human tumor cells with defined genetic elements
      Hahn, William C.; Counter, Christopher M.; Lundberg, Ante S.; Beijersbergen, Roderick L.; Brooks, Mary W.; Weinberg, Robert A.
      Nature (London) (1999), 400 (6743), 464-468CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
      During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes. However, similar expts. with human cells have consistently failed to yield tumorigenic transformants, indicating a fundamental difference in the biol. of human and rodent cells. The few reported successes in the creation of human tumor cells have depended on the use of chem. or phys. agents to achieve immortalization, the selection of rare, spontaneously arising immortalized cells, or the use of an entire viral genome. The authors show here that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.
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    22. 22
      Jung, K.-J.; Dasgupta, A.; Huang, K.; Jeong, S.-J.; Pise-Masison, C.; Gurova, K. V.; Brady, J. N. Small-Molecule Inhibitor Which Reactivates p53 in Human T-Cell Leukemia Virus Type 1-Transformed Cells. J. Virol. 2008, 82, 8537– 8547,  DOI: 10.1128/JVI.00690-08
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      Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells
      Jung, Kyung-Jin; Dasgupta, Arindam; Huang, Keven; Jeong, Soo-Jin; Pise-Masison, Cynthia; Gurova, Katerina V.; Brady, John N.
      Journal of Virology (2008), 82 (17), 8537-8547CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      Human T-cell leukemia virus type 1 (HTLV-1) is the etiol. agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the HTLV-1-encoded Tax protein inhibits the function of tumor suppressor p53 through a Tax-induced NF-κB pathway. Given these attributes, we were interested in the activity of small-mol. inhibitor 9-aminoacridine (9AA), an anticancer drug that targets two important stress response pathways, NF-κB and p53. In the present study, we have examd. the effects of 9AA on HTLV-1-transformed cells. Treatment of HTLV-1-transformed cells with 9AA resulted in a dramatic decrease in cell viability. Consistent with these results, we obsd. an increase in the percentage of cells in sub-G1 and an increase in the no. of cells pos. by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay following treatment of HTLV-1-transformed cells with 9AA. In each assay, HTLV-1-transformed cells C8166, Hut102, and MT2 were more sensitive to treatment with 9AA than control CEM and peripheral blood mononuclear cells. Analyzing p53 function, we demonstrate that treatment of HTLV-1-transformed cells with 9AA resulted in an increase in p53 protein and activation of p53 transcription activity. Of significance, 9AA-induced cell death could be blocked by introduction of a p53 small interfering RNA, linking p53 activity and cell death. These results suggest that Tax-repressed p53 function in HTLV-1-transformed cells is "druggable" and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-κB suggests a promising strategy for the treatment of HTLV-1-transformed cells.
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    23. 23
      Bhattacharya, K.; Weidenauer, L.; Luengo, T. M.; Pieters, E. C.; Echeverría, P. C.; Bernasconi, L.; Wider, D.; Sadian, Y.; Koopman, M. B.; Villemin, M.; Bauer, C.; Rüdiger, S. G. D.; Quadroni, M.; Picard, D. The Hsp70-Hsp90 Co-Chaperone Hop/Stip1 Shifts the Proteostatic Balance from Folding Towards Degradation. Nat. Commun. 2020, 11, 5975,  DOI: 10.1038/s41467-020-19783-w
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      The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation
      Bhattacharya, Kaushik; Weidenauer, Lorenz; Luengo, Tania Moran; Pieters, Ellis C.; Echeverria, Pablo C.; Bernasconi, Lilia; Wider, Diana; Sadian, Yashar; Koopman, Margreet B.; Villemin, Matthieu; Bauer, Christoph; Rudiger, Stefan G. D.; Quadroni, Manfredo; Picard, Didier
      Nature Communications (2020), 11 (1), 5975CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 mol. chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a no. of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70-Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures the proteostatic equil. Thus, cells may act on the level and/or activity of Hop to shift the proteostatic balance between folding and degrdn.
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    24. 24
      Mondal, S.; Bhattacharya, K.; Mandal, C. Nutritional Stress Reprograms Dedifferention in Glioblastoma Multiforme Driven by PTEN/Wnt/Hedgehog Axis: a Stochastic Model of Cancer Stem Cells. Cell Death Discovery 2018, 4, 110,  DOI: 10.1038/s41420-018-0126-6
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      Nutritional stress reprograms dedifferention in glioblastoma multiforme driven by PTEN/Wnt/Hedgehog axis: a stochastic model of cancer stem cells
      Mondal Susmita; Bhattacharya Kaushik; Mandal Chitra; Bhattacharya Kaushik
      Cell death discovery (2018), 4 (), 110 ISSN:2058-7716.
      The emergence and maintenance of cancer stem-like cells (CSCs) are usually governed by tumor niche. Tumor niche always provides metabolic challenges to cancer cells and CSCs mostly because of tissue hypoxia. However, the role of micro-environmental nutritional stress (NS) in dedifferentiation of cancer cells is poorly defined. Here, we developed a stochastic model of CSCs by gradual nutritional deprivation in glioblastoma multiforme (GBM) cells used as a model system. Nutritional deprivation induced enhanced expression of glioblastoma stem-like cells (GSCs)-specific biomarkers with higher invasive and angiogenic properties. This NS-induced cells showed higher xenobiotic efflux ability, and hence exhibit resistance to multiple anticancer drugs. In the molecular level, such NS activated Wnt and Hedgehog (Hh) signaling pathways by stabilizing β-catenin and Gli1, respectively, through modulation of GSK3β/AKT axis. GBM-specific PTEN (phosphatase and tensin homolog) mutation contributed to better phenoconversion toward GSCs. Knocking down of PTEN coupled with NS induction enhanced neurosphere formation, GSC-specific biomarker expressions, and activation of Wnt/Hh signaling. Thus, such an in-depth understanding of dedifferentiation of GBM cells to GSCs under NS suggested that targeting Wnt/Hh signaling possibly be a better therapeutic approach.
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    25. 25
      Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Preibisch, S.; Rueden, C.; Saalfeld, S.; Schmid, B.; Tinevez, J.-Y.; White, D. J.; Hartenstein, V.; Eliceiri, K.; Tomancak, P.; Cardona, A. Fiji: an Open-Source Platform for Biological-Image Analysis. Nat. Methods 2012, 9, 676– 682,  DOI: 10.1038/nmeth.2019
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      Fiji: an open-source platform for biological-image analysis
      Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin; Kaynig, Verena; Longair, Mark; Pietzsch, Tobias; Preibisch, Stephan; Rueden, Curtis; Saalfeld, Stephan; Schmid, Benjamin; Tinevez, Jean-Yves; White, Daniel James; Hartenstein, Volker; Eliceiri, Kevin; Tomancak, Pavel; Cardona, Albert
      Nature Methods (2012), 9 (7_part1), 676-682CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      Fiji is a distribution of the popular open-source software ImageJ focused on biol.-image anal. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biol. research communities.
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    26. 26
      Xie, J.; Pan, X.; Wang, M.; Ma, J.; Fei, Y.; Wang, P.-N.; Mi, L. The Role of Surface Modification for TiO2 Nanoparticles in Cancer Cells. Colloids Surf., B 2016, 143, 148– 155,  DOI: 10.1016/j.colsurfb.2016.03.029
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      The role of surface modification for TiO2 nanoparticles in cancer cells
      Xie, Jin; Pan, Xiaobo; Wang, Mengyan; Ma, Jiong; Fei, Yiyan; Wang, Pei-Nan; Mi, Lan
      Colloids and Surfaces, B: Biointerfaces (2016), 143 (), 148-155CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      Titanium dioxide nanoparticles (TiO2 NPs) have a potential in the field of biol. application. However, its poor dispersibility in water hampered its applications. In this study, 3-phosphonopropionic acid and 3-aminopropyl-triethoxysilane were resp. used for surface modification on TiO2 NPs with neg. and pos. surface charges (denoted as TiO2-COOH and TiO2-NH2). Zeta potentials of the prepd. samples with high abs. value demonstrate the great improvement in their dispersibility. In terms of viability expt., both TiO2-COOH and TiO2-NH2 showed low cytotoxicity. The cellular uptake efficiency and the uptake pathways of TiO2-COOH and TiO2-NH2 for cancer cells were studied. The exocytosis of TiO2-NH2 was also obsd. in the expt.
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    27. 27
      Joshi, A.; Dai, L.; Liu, Y.; Lee, J.; Ghahhari, N. M.; Segala, G.; Beebe, K.; Jenkins, L. M.; Lyons, G. C.; Bernasconi, L.; Tsai, F. T. F.; Agard, D. A.; Neckers, L.; Picard, D. The Mitochondrial HSP90 Paralog TRAP1 Forms an OXPHOS-Regulated Tetramer and is Involved in Mitochondrial Metabolic Homeostasis. BMC Biol. 2020, 18, 10,  DOI: 10.1186/s12915-020-0740-7
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      The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
      Joshi, Abhinav; Dai, Li; Liu, Yanxin; Lee, Jungsoon; Ghahhari, Nastaran Mohammadi; Segala, Gregory; Beebe, Kristin; Jenkins, Lisa M.; Lyons, Gaelyn C.; Bernasconi, Lilia; Tsai, Francis T. F.; Agard, David A.; Neckers, Len; Picard, Didier
      BMC Biology (2020), 18 (1), 10CODEN: BBMIF7; ISSN:1741-7007. (BioMed Central Ltd.)
      Abstr.: Background: The mol. chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metab. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive anal. of the TRAP1 interactome and of how TRAP1 and mitochondrial metab. mutually affect each other. Results: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metab. to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quant. by far, the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline and an increase in OXPHOS. Conclusions: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metab.
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    28. 28
      Yoshida, S.; Tsutsumi, S.; Muhlebach, G.; Sourbier, C.; Lee, M.-J.; Lee, S.; Vartholomaiou, E.; Tatokoro, M.; Beebe, K.; Miyajima, N.; Mohney, R. P.; Chen, Y.; Hasumi, H.; Xu, W.; Fukushima, H.; Nakamura, K.; Koga, F.; Kihara, K.; Trepel, J.; Picard, D.; Neckers, L. Molecular Chaperone TRAP1 Regulates a Metabolic Switch Between Mitochondrial Respiration and Aerobic Glycolysis. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E1604– E1612,  DOI: 10.1073/pnas.1220659110
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      Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis
      Yoshida, Soichiro; Tsutsumi, Shinji; Muhlebach, Guillaume; Sourbier, Carole; Lee, Min-Jung; Lee, Sunmin; Vartholomaiou, Evangelia; Tatokoro, Manabu; Beebe, Kristin; Miyajima, Naoto; Mohney, Robert P.; Chen, Yang; Hasumi, Hisashi; Xu, Wanping; Fukushima, Hiroshi; Nakamura, Ken; Koga, Fumitaka; Kihara, Kazunori; Trepel, Jane; Picard, Didier; Neckers, Leonard
      Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (17), E1604-E1612, SE1604/1-SE1604/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      TRAP1 (TNF receptor-assocd. protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer mol. target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidn., and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metab. is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial mol. chaperone may act as a tumor suppressor.
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      Bhattacharya, K.; Bag, A. K.; Tripathi, R.; Samanta, S. K.; Pal, B. C.; Shaha, C.; Mandal, C. Mahanine, a Novel Mitochondrial Complex-III Inhibitor Induces G0/G1 Arrest Through Redox Alteration-Mediated DNA Damage Response and Regresses Glioblastoma Multiforme. Am. J. Cancer Res. 2014, 4, 629– 647
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      Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme
      Bhattacharya Kaushik; Bag Arup K; Samanta Suman K; Mandal Chitra; Tripathi Rakshamani; Shaha Chandrima; Pal Bikas C
      American journal of cancer research (2014), 4 (6), 629-47 ISSN:2156-6976.
      The Electron transport chain (ETC) is responsible for oxidative phosphorylation-mediated mitochondrial respiration. Here we wanted to address the mahanine-induced targeted pathways in glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated mahanine, as a novel mitochondrial complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of mahanine. During G0/G1 arrest, other hallmark proteins like, cyclin D1/cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of mahanine was also established in in vivo mice model. Mahanine-induced complex-III inhibition triggered enhanced ROS in hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that mahanine-treated G0/G1 arrested cells were less potent to form xenograft tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage. Taken together, our results established that complex-III of ETC is one of the possible potential targets of mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes.
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      Tofanelli, M. A.; Ackerson, C. J. Superatom Electron Configuration Predicts Thermal Stability of Au25(SR)18 Nanoclusters. J. Am. Chem. Soc. 2012, 134, 16937– 16940,  DOI: 10.1021/ja3072644
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      Superatom Electron Configuration Predicts Thermal Stability of Au25(SR)18 Nanoclusters
      Tofanelli, Marcus A.; Ackerson, Christopher J.
      Journal of the American Chemical Society (2012), 134 (41), 16937-16940CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The exceptional stability of ligand-stabilized gold nanoclusters such as Au25(SC6H13)18-, Au39(PR3)14X6-, and Au102(SR)44 arises from the total filling of superat. electron shells, resulting in a "noble-gas superatom" electron configuration. Electrochem. manipulation of the oxidn. state can add or remove electrons from superatom orbitals, creating species electronically analogous to at. radicals. Herein we show that oxidizing the Au25(SR)18- superatom from the noble-gas-like 1S21P6 electron configuration to the open-shell radical 1S21P5 and diradical 1S21P4 configurations results in decreased thermal stability of the compd., as measured by differential scanning calorimetry. Similar expts. probing five oxidn. states of the putatively geometrically stabilized Au144(SR)60 cluster suggest a more complex relationship between oxidn. state and thermal stability for this compd.
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      Tofanelli, M. A.; Salorinne, K.; Ni, T. W.; Malola, S.; Newell, B.; Phillips, B.; Häkkinen, H.; Ackerson, C. J. Jahn–Teller Effects in Au25(SR)18. Chem. Sci. 2016, 7, 1882– 1890,  DOI: 10.1039/C5SC02134K
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      Jahn-Teller effects in Au25(SR)18
      Tofanelli, Marcus A.; Salorinne, Kirsi; Ni, Thomas W.; Malola, Sami; Newell, Brian; Phillips, Billy; Hakkinen, Hannu; Ackerson, Christopher J.
      Chemical Science (2016), 7 (3), 1882-1890CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A review. The relationship between oxidn. state, structure, and magnetism in many mols. is well described by first-order Jahn-Teller distortions. This relationship is not yet well defined for ligated nanoclusters and nanoparticles, esp. the nano-technol. relevant gold-thiolate protected metal clusters. Here we interrogate the relationships between structure, magnetism, and oxidn. state for the three stable oxidn. states, -1, 0 and +1 of the thiolate protected nanocluster Au25(SR)18. We present the single crystal X-ray structures of the previously undetd. charge state Au25(SR)18+1, as well as a higher quality single crystal structure of the neutral compd. Au25(SR)180. Structural data combined with SQUID magnetometry and DFT theory enable a complete description of the optical and magnetic properties of Au25(SR)18 in the three oxidn. states. In aggregate the data suggests a first-order Jahn-Teller distortion in this compd. The high quality single crystal X-ray structure enables an anal. of the ligand-ligand and ligand-cluster packing interactions that underlie single-crystal formation in thiolate protected metal clusters.
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    32. 32
      Shibu, E. S.; Muhammed, M. A. H.; Tsukuda, T.; Pradeep, T. J. Phys. Chem. C 2008, 112, 12168– 12176,  DOI: 10.1021/jp800508d
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      Ligand Exchange of Au25SG18 Leading to Functionalized Gold Clusters: Spectroscopy, Kinetics, and Luminescence
      Shibu, E. S.; Muhammed, M. A. Habeeb; Tsukuda, T.; Pradeep, T.
      Journal of Physical Chemistry C (2008), 112 (32), 12168-12176CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Ligand exchange offers an effective way to modify the properties of the recently prepd. quantum clusters of Au. To tune optical and photoluminescence properties of one of the most stable quantum clusters of Au, Au25SG18 (SG-glutathione thiolate), the authors functionalized it by the exchange of -SG with functionalized -SG and with an altogether different ligand, namely, 3-mercapto-2-butanol (MB). The products were characterized by various techniques such as optical absorption (UV-visible), FTIR, NMR, x-ray photoelectron (XPS), and luminescence spectroscopies, mass spectrometry, and TG. Analyses of the TG data helped to establish the mol. compn. of the products. Ligand exchange reaction was monitored by NMR spectroscopy, and the exchange reaction follows a 1st order kinetics. The XPS study showed that after the exchange reaction there was no change in the chem. nature of the metal core and binding energy values of Au 4f7/2 and 4f5/2, which are similar in both the parent and the exchanged products. Photoluminescence studies of these clusters, done in the aerated conditions, showed that the excitation spectrum of the MB-exchanged product is entirely different from the acetyl- and formyl-glutathione exchanged products. The inherent fluorescence and solid-state emission of these clusters were obsd. This intense emission allows optical imaging of the material in the solid state. The emission is strongly temp. dependent. The synthesis of a diverse variety of clusters and their chem. stability and intense luminescence offer numerous applications in areas such as energy transfer, sensors, biolabeling, and drug delivery.
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    33. 33
      Tay, C. Y.; Yu, Y.; Setyawati, M. I.; Xie, J.; Leong, D. T. Presentation Matters: Identity of Gold Nanocluster Capping Agent Governs Intracellular Uptake and Cell Metabolism. Nano Res. 2014, 7, 805– 815,  DOI: 10.1007/s12274-014-0441-z
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      Presentation matters: Identity of gold nanocluster capping agent governs intracellular uptake and cell metabolism
      Tay, Chor Yong; Yu, Yong; Setyawati, Magdiel Inggrid; Xie, Jianping; Leong, David Tai
      Nano Research (2014), 7 (6), 805-815CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
      Au nanoclusters (AuNCs) hold tremendous potential to be employed in a wide variety of biol. applications. Despite the rapid development in the field of NCs synthesis, a comprehensive understanding of how cells interact with this class of ultra-small nanoparticles (<2 nm) having defined sizes and surface chem., remains poorly understood. In this study, we show that the choice of the surface ligand used to protect AuNCs can significantly perturb cellular uptake and intracellular redox signaling. A panel of monodisperse, atomically precise AuNCs with different core Au atom no. (i.e., Au15, Au18 and Au25) protected with either mercaptopropionic acid (MPA) or glutathione (GSH) capping agent were synthesized and their effects on the generation of intracellular reactive oxygen species (ROS), cytotoxicity and genotoxicity of the NCs were assessed. Both mitochondrial superoxide anion (O2·-) and cytoplasmic ROS were found to be higher in cells exposed to MPA but not GSH capped AuNCs. The unregulated state of intracellular ROS is correlated to the amt. of internalized AuNCs. Interestingly, MPA-AuNCs induction of ROS level did not lead to any detrimental cellular effects such as cell death or DNA damage. Instead, it was obsd. that the increase in redox status corresponded to higher cellular metab. and proliferative capacity. Our study illustrates that surface chem. of AuNCs plays a pivotal role in affecting the biol. outcomes and the new insights gained will be useful to form the basis of defining specific design rules to enable rational engineering of ultra-small complex nanostructures for biol. applications. [Figure not available: see fulltext.].
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      Sabuncu, A. C.; Grubbs, J.; Qian, S.; Abdel-Fattah, T. M.; Stacey, M. W.; Beskok, A. Probing Nanoparticle Interactions in Cell Culture Media. Colloids Surf., B 2012, 95, 96– 102,  DOI: 10.1016/j.colsurfb.2012.02.022
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      Probing nanoparticle interactions in cell culture media
      Sabuncu, Ahmet C.; Grubbs, Janna; Qian, Shizhi; Abdel-Fattah, Tarek M.; Stacey, Michael W.; Beskok, Ali
      Colloids and Surfaces, B: Biointerfaces (2012), 95 (), 96-102CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      Nanoparticle research is often performed in vitro with little emphasis on the potential role of cell culture medium. In this study, gold nanoparticle interactions with cell culture medium and 2 cancer cell lines (human T-cell leukemia Jurkat and human pancreatic carcinoma PANC1) were investigated. Gold nanoparticles of 10, 25, 50, and 100 nm in diam. at fixed mass concn. were tested. Size distributions and zeta potentials of gold nanoparticles suspended in deionized (DI) water and Dulbecco's Modified Eagle's Media (DMEM) supplemented with fetal calf serum (FCS) were measured using dynamic light scattering (DLS) technique. In DI water, particle size distributions exhibited peaks around their nominal diams. However, the gold nanoparticles suspended in DMEM supplemented with FCS formed complexes around 100 nm, regardless of their nominal sizes. The DLS and UV-vis spectroscopy results indicate gold nanoparticle agglomeration in DMEM that is not supplemented by FCS. The zeta potential results indicate that protein rich FCS increases the dispersion quality of gold nanoparticle suspensions through steric effects. Cellular uptake of 25 and 50 nm gold nanoparticles by Jurkat and PANC1 cell lines were investigated using inductively coupled plasma-mass spectroscopy. The intracellular gold level of PANC1 cells was higher than that of Jurkat cells, where 50 nm particles enter cells at faster rates than the 25 nm particles.
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      Wang, M.; Wu, Z.; Yang, J.; Wang, G.; Wang, H.; Cai, W. Au25(SG)18 as a Fluorescent Iodide Sensor. Nanoscale 2012, 4, 4087– 4090,  DOI: 10.1039/c2nr30169e
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      Au25(SG)18 as a fluorescent iodide sensor
      Wang, Man; Wu, Zhikun; Yang, Jiao; Wang, Guozhong; Wang, Hongzhi; Cai, Weiping
      Nanoscale (2012), 4 (14), 4087-4090CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      The recently emerging gold nanoclusters (GNC) are of major importance for both basic science studies and practical applications. Based on its surface-induced fluorescence properties, the potential use of Au25(SG)18 (GSH: glutathione) as a fluorescent iodide sensor was studied. The current detection limit of 400 nM, which can possibly be further enhanced by optimizing the conditions, and excellent selectivity among 12 types of anions (F-, Cl-, Br-, I-, NO3-, ClO4-, HCO3-, IO3-, SO42-, SO32-, AcO- and C6H5O73-) make Au25(SG)18 a good candidate for iodide sensing. Also, the work revealed the particular sensing mechanism, which is affinity-induced ratiometric and enhanced fluorescence (abbreviated to AIREF), which has rarely been reported previously and may provide an alternative strategy for devising nanoparticle-based sensors.
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      Dalal, C.; Saha, A.; Jana, N. R. Nanoparticle Multivalency Directed Shifting of Cellular Uptake Mechanism. J. Phys. Chem. C 2016, 120, 6778– 6786,  DOI: 10.1021/acs.jpcc.5b11059
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      Nanoparticle Multivalency Directed Shifting of Cellular Uptake Mechanism
      Dalal, Chumki; Saha, Arindam; Jana, Nikhil R.
      Journal of Physical Chemistry C (2016), 120 (12), 6778-6786CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Although nanoparticle multivalency is known to influence their biol. labeling performance, the functional role of multivalency is largely unexplored. Here we show that the folate receptor mediated cellular internalization mechanism of 35-50 nm nanoparticle shifts from caveolae- to clathrin-mediated endocytosis as the nanoparticle multivalency increases from 10 to 40 and results in the difference of their subcellular trafficking. We have synthesized folate functionalized multivalent quantum dot (QD) with varied av. nos. of folate per QD between 10 and 110 [e.g., QD(folate)10, QD(folate)20, QD(folate)40, QD(folate)110] and investigated their uptake and localization into folate receptor overexpressed HeLa and KB cells. We found that uptake of QD(folate)10 occurs predominantly via caveolae-mediated endocytosis and entirely trafficked to the perinuclear region. In contrast, uptake of QD(folate)20 occurs via both caveolae- and chathrin-mediated endocytosis; uptake of QD(folate)40 and QD(folate)110 occurs predominantly via clathrin-mediated endocytosis and these three QDs localize predominantly at lysosome with restricted trafficking to the perinuclear region. This work shows the functional role of multivalent interaction in cellular endocytosis and intracellular trafficking which can be exploited for subcellular targeting applications.
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    37. 37
      Bera, K.; Maiti, S.; Maity, M.; Mandal, C.; Maiti, N. C. Porphyrin–Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells. ACS Omega 2018, 3, 4602– 4619,  DOI: 10.1021/acsomega.8b00419
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      Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells
      Bera, Kaushik; Maiti, Samarpan; Maity, Mritunjoy; Mandal, Chitra; Maiti, Nakul C.
      ACS Omega (2018), 3 (4), 4602-4619CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with a tetrasodium salt of meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles. Porphyrin interacts with the gold nanosurface through the coordination interaction between gold and pyrrolic nitrogen atoms of the porphyrin and forms a strong assocn. complex. DOX-loaded nanocomposite DOX@TPPS-AuNPs demonstrated enhanced cellular uptake with significantly reduced drug efflux in MDR brain cancer cells, thereby increasing the retention time of the drug within tumor cells. It exhibited about 9 times greater potency for cellular apoptosis via triggered release commenced by acidic pH. DOX has been successfully loaded on the porphyrin-modified gold nanosurface noncovalently with high encapsulation efficacy (∼90%) and tightly assocd. under normal physiol. conditions but capable of releasing ∼81% of drug in a low-pH environment. Subsequently, DOX-loaded TPPS-AuNPs exhibited higher inhibition of cellular metastasis, invasion, and angiogenesis, suggesting that TPPS-modified AuNPs could improve the therapeutic efficacy of the drug mol. Unlike free DOX, drug-loaded TPPS-AuNPs did not show toxicity toward normal cells. Therefore, higher drug encapsulation efficacy with selective targeting potential and acidic-pH-mediated intracellular release of DOX at the nucleus make TPPS-AuNPs a "magic bullet" for implication in nanomedicine.
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      Von Kleist, L.; Stahlschmidt, W.; Bulut, H.; Gromova, K.; Puchkov, D.; Robertson, M. J.; MacGregor, K. A.; Tomilin, N.; Pechstein, A.; Chau, N.; Chircop, M.; Sakoff, J.; Peter von Kries, J.; Saenger, W.; Kräusslich, H.-G.; Shupliakov, O.; Robinson, P. J.; McCluskey, A.; Haucke, V. Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition. Cell 2011, 146, 841,  DOI: 10.1016/j.cell.2011.08.014
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      Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition [Erratum to document cited in CA155:427405]
      von Kleist, Lisa; Stahlschmidt, Wiebke; Bulut, Haydar; Gromova, Kira; Puchkov, Dmytro; Robertson, Mark J.; MacGregor, Kylie A.; Tomilin, Nikolay; Pechstein, Arndt; Chau, Ngoc; Chircop, Megan; Sakoff, Jennette; Peter von Kries, Jens; Saenger, Wolfram; Kraeusslich, Hans-Georg; Shupliakov, Oleg; Robinson, Phillip J.; McCluskey, Adam; Haucke, Volker
      Cell (Cambridge, MA, United States) (2011), 146 (5), 841CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      On page 471, the eighth author's name contained an error; the cor. author list is given.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFakurrF&md5=28b5a503fe4943177f56be33cd8147c9
    39. 39
      Preta, G.; Cronin, J. G.; Sheldon, I. M. Dynasore - Not Just a Dynamin Inhibitor. Cell Commun. Signaling 2015, 13, 24,  DOI: 10.1186/s12964-015-0102-1
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      Dynasore - not just a dynamin inhibitor
      Preta Giulio; Cronin James G; Sheldon I Martin
      Cell communication and signaling : CCS (2015), 13 (), 24 ISSN:.
      Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals evidence that dynasore reduces labile cholesterol in the plasma membrane, and disrupts lipid raft organization, in a dynamin-independent manner. To explore the role of dynamin it is important to use multiple dynamin inhibitors, alongside the use of dynamin mutants and RNA interference targeting genes encoding dynamin. On the other hand, dynasore provides an interesting tool to explore the regulation of cholesterol in plasma membranes.
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    40. 40
      Kuhn, D. A.; Vanhecke, D.; Michen, B.; Blank, F.; Gehr, P.; Petri-Fink, A.; Rothen-Rutishauser, B. Different Endocytotic Uptake Mechanisms for Nanoparticles in Epithelial Cells and Macrophages. Beilstein J. Nanotechnol. 2014, 5, 1625– 1636,  DOI: 10.3762/bjnano.5.174
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      40
      Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages
      Kuhn, Dagmar A.; Vanhecke, Dimitri; Michen, Benjamin; Blank, Fabian; Gehr, Peter; Petri-Fink, Alke; Rothen-Rutishauser, Barbara
      Beilstein Journal of Nanotechnology (2014), 5 (), 1625-1636, 12 pp.CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
      Precise knowledge regarding cellular uptake of nanoparticles is of great importance for future biomedical applications. Four different endocytotic uptake mechanisms, i.e., phagocytosis, macropinocytosis, clathrin- and caveolin-mediated endocytosis, were investigated using a mouse macrophage (J774A.1) and a human alveolar epithelial type II cell line (A549). In order to deduce the involved pathway in nanoparticle uptake, selected inhibitors specific for one of the endocytotic pathways were optimized regarding concn. and incubation time in combination with fluorescently tagged marker proteins. Qual. immunolocalization showed that J774A.1 cells highly expressed the lipid raft-related protein flotillin-1 and clathrin heavy chain, however, no caveolin-1. A549 cells expressed clathrin heavy chain and caveolin-1, but no flotillin-1 uptake-related proteins. Our data revealed an impeded uptake of 40 nm polystyrene nanoparticles by J774A.1 macrophages when actin polymn. and clathrin-coated pit formation was blocked. From this result, it is suggested that macropinocytosis and phagocytosis, as well as clathrin-mediated endocytosis, play a crucial role. The uptake of 40 nm nanoparticles in alveolar epithelial A549 cells was inhibited after depletion of cholesterol in the plasma membrane (preventing caveolin-mediated endocytosis) and inhibition of clathrin-coated vesicles (preventing clathrin-mediated endocytosis). Our data showed that a combination of several distinguishable endocytotic uptake mechanisms are involved in the uptake of 40 nm polystyrene nanoparticles in both the macrophage and epithelial cell line.
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      Nolfi-Donegan, D.; Braganza, A.; Shiva, S. Mitochondrial Electron Transport Chain: Oxidative Phosphorylation, Oxidant Production, and Methods of Measurement. Redox Biol. 2020, 37, 101674  DOI: 10.1016/j.redox.2020.101674
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      Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement
      Nolfi-Donegan, Deirdre; Braganza, Andrea; Shiva, Sruti
      Redox Biology (2020), 37 (), 101674CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
      A review. The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of electron transfer is the generation of reactive oxygen species (ROS), which contributes to both homeostatic signaling as well as oxidative stress during pathol. In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS prodn. by the electron transport chain. We also outline traditional and novel translational methodol. for assessing mitochondrial energetics in health and disease.
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      Zhao, Y.; Butler, E. B.; Tan, M. Targeting Cellular Metabolism to Improve Cancer Therapeutics. Cell Death Discovery 2013, 4, e532  DOI: 10.1038/cddis.2013.60
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      42
      Targeting cellular metabolism to improve cancer therapeutics
      Zhao, Y.; Butler, E. B.; Tan, M.
      Cell Death & Disease (2013), 4 (March), e532CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
      A review. The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy prodn. in cancer cells is abnormally dependent on aerobic glycolysis. In addn. to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metab. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metab., fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metab. may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metab. inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metab. in therapeutic resistance, which is a highly clin. relevant area in cancer metab. research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metab. and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
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      Guo, R.; Gu, J.; Zong, S.; Wu, M.; Yang, M. Structure and Mechanism of Mitochondrial Electron Transport Chain. Biomed. J. 2018, 41, 9– 20,  DOI: 10.1016/j.bj.2017.12.001
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      Structure and mechanism of mitochondrial electron transport chain
      Guo Runyu; Gu Jinke; Zong Shuai; Wu Meng; Yang Maojun
      Biomedical journal (2018), 41 (1), 9-20 ISSN:.
      Respiration is one of the most vital and basic features of living organisms. In mammals, respiration is accomplished by respiratory chain complexes located on the mitochondrial inner membrane. In the past century, scientists put tremendous efforts in understanding these complexes, but failed to solve the high resolution structure until recently. In 2016, three research groups reported the structure of respiratory chain supercomplex from different species, and fortunately the structure solved by our group has the highest resolution. In this review, we will compare the recently solved structures of respirasome, probe into the relationship between cristae shape and respiratory chain organization, and discuss the highly disputed issues afterwards. Besides, our group reported the first high resolution structure of respirasome and medium resolution structure of megacomplex from cultured human cells this year. Definitely, these supercomplex structures will provide precious information for conquering the mitochondrial malfunction diseases.
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      Zhao, R. Z.; Jiang, S.; Zhang, L.; Yu, Z.-B. Mitochondrial Electron Transport Chain, ROS Generation and Uncoupling (Review). Int. J. Mol. Med. 2019, 44, 3– 15,  DOI: 10.3892/ijmm.2019.4188
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      Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
      Zhao, Ru-zhou; Jiang, Shuai; Zhang, Lin; Yu, Zhi-bin
      International Journal of Molecular Medicine (2019), 44 (1), 3-15CODEN: IJMMFG; ISSN:1791-244X. (Spandidos Publications Ltd.)
      A review. The mammalian mitochondrial electron transport chain (ETC) includes complexes I-IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I-IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiol. and pathol. regulation of ROS. As signaling mols., ROS play an important role in cell proliferation, hypoxia adaptation and cell fate detn., but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a no. of diseases are closely related to ROS overprodn. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1-5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temp. in a cold environment through non-shivering thermogenesis. The core role of UCP2-5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are assocd. with UCPs.
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      Yépez, V. A.; Kremer, L. S.; Iuso, A.; Gusic, M.; Kopajtich, R.; Koňaříková, E.; Nadel, A.; Wachutka, L.; Prokisch, H.; Gagneur, J. OCR-Stats: Robust Estimation and Statistical Testing of Mitochondrial Respiration Activities Using Seahorse XF Analyzer. PLoS One 2018, 13, e0199938  DOI: 10.1371/journal.pone.0199938
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      OCR-Stats: robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer
      Yepez, Vicente A.; Kremer, Laura S.; Iuso, Arcangela; Gusic, Mirjana; Kopajtich, Robert; Konarikova, Elisaka; Nadel, Agnieszka; Wachutka, Leonhard; Prokisch, Holger; Gagneur, Julien
      PLoS One (2018), 13 (7), e0199938/1-e0199938/18CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The accurate quantification of cellular and mitochondrial bioenergetic activity is of great interest in medicine and biol. Mitochondrial stress tests performed with Seahorse Bioscience XF Analyzers allow the estn. of different bioenergetic measures by monitoring the oxygen consumption rates (OCR) of living cells in multi-well plates. However, studies of the statistical best practices for detg. aggregated OCR measurements and comparisons have been lacking. Therefore, to understand how OCR behaves across different biol. samples, wells, and plates, we performed mitochondrial stress tests in 126 96-well plates involving 203 fibroblast cell lines. We show that the noise of OCR is multiplicative, that outlier data points can concern individual measurements or all measurements of a well, and that the inter-plate variation is greater than the intra-plate variation. Based on these insights, we developed a novel statistical method, OCR-Stats, that: (i) robustly ests. OCR levels modeling multiplicative noise and automatically identifying outlier data points and outlier wells; and (ii) performs statistical testing between samples, taking into account the different magnitudes of the between- and within-plate variations. This led to a significant redn. of the coeff. of variation across plates of basal respiration by 45% and of maximal respiration by 29%. Moreover, using pos. and neg. controls, we show that our statistical test outperforms the existing methods.
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      Pike Winer, L. S.; Wu, M. Rapid Analysis of Glycolytic and Oxidative Substrate Flux of Cancer Cells in a Microplate. PLoS One 2014, 9, e109916  DOI: 10.1371/journal.pone.0109916
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      Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate
      Pike Winer, Lisa S.; Wu, Min
      PLoS One (2014), 9 (10), e109916/1-e109916/14, 14 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Cancer cells exhibit remarkable alterations in cellular metab., particularly in their nutrient substrate preference. We have devised several exptl. methods that rapidly analyze the metabolic substrate flux in cancer cells: glycolysis and the oxidn. of major fuel substrates glucose, glutamine, and fatty acids. Using the XF Extracellular Flux analyzer, these methods measure, in real-time, the oxygen consumption rate OCR and extracellular acidification rate ECAR of living cells in a microplate as they respond to substrates and metabolic perturbation agents. In proof-of-principle expts., we analyzed substrate flux and mitochondrial bioenergetics of two human glioblastoma cell lines, SF188s and SF188f, which were derived from the same parental cell line but proliferate at slow and fast rates, resp. These analyses led to three interesting observations: (1) both cell lines respired effectively with substantial endogenous substrate respiration; (2) SF188f cells underwent a significant shift from glycolytic to oxidative metab., along with a high rate of glutamine oxidn. relative to SF188s cells; and (3) the mitochondrial proton leak-linked respiration of SF188f cells increased significantly compared to SF188s cells. It is plausible that the proton leak of SF188f cells may play a role in allowing continuous glutamine-fueled anaplerotic TCA cycle flux by partially uncoupling the TCA cycle from oxidative phosphorylation. Taken together, these rapid, sensitive and high-throughput substrate flux anal. methods introduce highly valuable approaches for developing a greater understanding of genetic and epigenetic pathways that regulate cellular metab., and the development of therapies that target cancer metab.
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      Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J. S.; Hileman, E. O.; Plunkett, W.; Keating, M. J.; Huang, P. Inhibition of Mitochondrial Respiration: a Novel Strategy to Enhance Drug-Induced Apoptosis in Human Leukemia Cells by a Reactive Oxygen Species-Mediated Mechanism. J. Biol. Chem. 2003, 278, 37832– 37839,  DOI: 10.1074/jbc.M301546200
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      Inhibition of Mitochondrial Respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism
      Pelicano, Helene; Feng, Li; Zhou, Yan; Carew, Jennifer S.; Hileman, Elizabeth O.; Plunkett, William; Keating, Michael J.; Huang, Peng
      Journal of Biological Chemistry (2003), 278 (39), 37832-37839CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Cancer cells are under intrinsic increased oxidative stress and vulnerable to free radical-induced apoptosis. Here, the authors report a strategy to hinder mitochondrial electron transport and increase superoxide radical generation in human leukemia cells as a novel mechanism to enhance apoptosis induced by anticancer agents. This strategy was first tested in a proof-of-principle study using rotenone, a specific inhibitor of mitochondrial electron transport complex I. Partial inhibition of mitochondrial respiration enhances electron leakage from the transport chain, leading to an increase in generation and sensitization of the leukemia cells to anticancer agents whose action involve free radical generation. Using leukemia cells with genetic alterations in mitochondrial DNA and biochem. approaches, the authors further demonstrated that As2O3, a clin. active anti-leukemia agent, inhibits mitochondrial respiratory function, increases free radical generation, and enhances the activity of another agent against cultured leukemia cells and primary leukemia cells isolated from patients. The authors study shows that interfering mitochondrial respiration is a novel mechanism by which As2O3 increases generation of free radicals. This novel mechanism of action provides a biochem. basis for developing new drug combination strategies using As2O3 to enhance the activity of anticancer agents by promoting generation of free radicals.
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      Kausar, S.; Wang, F.; Cui, H. The Role of Mitochondria in Reactive Oxygen Species Generation and Its Implications for Neurodegenerative Diseases. Cell 2018, 7, 274,  DOI: 10.3390/cells7120274
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      The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases
      Kausar, Saima; Wang, Feng; Cui, Hongjuan
      Cells (2018), 7 (12), 274CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
      Mitochondria are dynamic cellular organelles that consistently migrate, fuse, and divide to modulate their no., size, and shape. In addn., they produce ATP, reactive oxygen species, and also have a biol. role in antioxidant activities and Ca2+ buffering. Mitochondria are thought to play a crucial biol. role in most neurodegenerative disorders. Neurons, being high-energy-demanding cells, are closely related to the maintenance, dynamics, and functions of mitochondria. Thus, impairment of mitochondrial activities is assocd. with neurodegenerative diseases, pointing to the significance of mitochondrial functions in normal cell physiol. In recent years, considerable progress has been made in our knowledge of mitochondrial functions, which has raised interest in defining the involvement of mitochondrial dysfunction in neurodegenerative diseases. Here, we summarize the existing knowledge of the mitochondrial function in reactive oxygen species generation and its involvement in the development of neurodegenerative diseases.
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      Zorov, D. B.; Juhaszova, M.; Sollott, S. J. Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release. Physiol. Rev. 2014, 94, 909– 950,  DOI: 10.1152/physrev.00026.2013
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      Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release
      Zorov, Dmitry B.; Juhaszova, Magdalena; Sollott, Steven J.
      Physiological Reviews (2014), 94 (3), 909-950CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
      A review. Byproducts of normal mitochondrial metab. and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiol. role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-assocd. ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiol. role by removal of unwanted cells or damaged mitochondria, or cause the pathol. elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS prodn. in vivo.
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      Hu, L.; Han, S.; Parveen, S.; Yuan, Y.; Zhang, L.; Xu, G. Highly Sensitive Fluorescent Detection of Trypsin Based on BSA-Stabilized Gold Nanoclusters. Biosens. Bioelectron. 2012, 32, 297– 299,  DOI: 10.1016/j.bios.2011.12.007
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      Highly sensitive fluorescent detection of trypsin based on BSA-stabilized gold nanoclusters
      Hu, Lianzhe; Han, Shuang; Parveen, Saima; Yuan, Yali; Zhang, Ling; Xu, Guobao
      Biosensors & Bioelectronics (2012), 32 (1), 297-299CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      In this study, fluorescent metal nanoclusters are presented as novel probes for sensitive detection of protease for the first time. The sensing mechanism is based on trypsin digestion of the protein template of BSA-stabilized Au nanoclusters. The decrease in fluorescence intensity of BSA-Au nanoclusters caused by trypsin allows the sensitive detection of trypsin in the range of 0.01-100 μg/mL. The detection limit for trypsin is 2 ng/mL (86 pM) at a signal-to-noise ratio of 3. The present nanosensor for trypsin detection possesses red emission, excellent biocompatibility, high selectivity, and good stability. In addn., we demonstrated the application of the present approach in real urine samples, which suggested its potential for diagnostic purposes.
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      McDonagh, B. H.; Singh, G.; Bandyopadhyay, S.; Lystvet, S. M.; Ryan, J. A.; Volden, S.; Kim, E.; Sandvig, I.; Sandvig, A.; Glomm, W. R. Controlling the Self-Assembly and Optical Properties of Gold Nanoclusters and Gold Nanoparticles Biomineralized with Bovine Serum Albumin. RSC Adv. 2015, 5, 101101– 101109,  DOI: 10.1039/C5RA23423A
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      Controlling the self-assembly and optical properties of gold nanoclusters and gold nanoparticles biomineralized with bovine serum albumin
      McDonagh, Birgitte H.; Singh, Gurvinder; Bandyopadhyay, Sulalit; Lystvet, Sina M.; Ryan, Joseph A.; Volden, Sondre; Kim, Eugene; Sandvig, Ioanna; Sandvig, Axel; Glomm, Wilhelm R.
      RSC Advances (2015), 5 (122), 101101-101109CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      While the size-dependent optical properties of BSA-stabilized gold nanoclusters are well known, the time-dependent growth mechanism remains to be described. Herein, we systematically compare two synthesis methods with and without ascorbic acid, and show that tuning of BSA-stabilized gold nanoclusters (AuNCs) of different sizes can be performed without the aid of an extrinsic reducing agent and with good reproducibility. We also show that adding ascorbic acid yields larger BSA-stabilized gold nanoparticles (AuNPs), and that AuNPs can only form above a threshold gold precursor concn. Using computed tomog., we describe how these biomineralized AuNPs show size-dependent X-ray attenuation. Growth of BSA-stabilized AuNCs and AuNPs, over a range of gold precursor concns., was followed with steady-state fluorescence and UV-vis spectroscopy for one week, constituting the first study of its kind. Based on our results, we propose a mechanism for BSA-stabilization of AuNCs and AuNPs that can further aid in selective growth of discrete AuNCs and AuNPs.
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      Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in Cancer Therapy: The Bright Side of the Moon. Exp. Mol. Med. 2020, 52, 192– 203,  DOI: 10.1038/s12276-020-0384-2
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      ROS in cancer therapy: the bright side of the moon
      Perillo, Bruno; Di Donato, Marzia; Pezone, Antonio; Di Zazzo, Erika; Giovannelli, Pia; Galasso, Giovanni; Castoria, Gabriella; Migliaccio, Antimo
      Experimental & Molecular Medicine (2020), 52 (2), 192-203CODEN: EMMEF3; ISSN:2092-6413. (Nature Research)
      A review. Reactive oxygen species constitute a group of highly reactive mols. that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The prodn. of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymic and nonenzymic pathways in the same cells. Moderate increases of ROS contribute to several pathol. conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the mol. mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.
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      Yang, H.; Villani, R. M.; Wang, H.; Simpson, M. J.; Roberts, M. S.; Tang, M.; Liang, X. The Role of Cellular Reactive Oxygen Species in Cancer Chemotherapy. J. Exp. Clin. Cancer Res. 2018, 37, 266,  DOI: 10.1186/s13046-018-0909-x
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      The role of cellular reactive oxygen species in cancer chemotherapy
      Yang, Haotian; Villani, Rehan M.; Wang, Haolu; Simpson, Matthew J.; Roberts, Michael S.; Tang, Min; Liang, Xiaowen
      Journal of Experimental & Clinical Cancer Research (2018), 37 (), 266CODEN: JECRDN; ISSN:1756-9966. (BioMed Central Ltd.)
      A review. Most chemotherapeutics elevate intracellular levels of reactive oxygen species (ROS), and many can alter redox-homeostasis of cancer cells. It is widely accepted that the anticancer effect of these chemotherapeutics is due to the induction of oxidative stress and ROS-mediated cell injury in cancer. However, various new therapeutic approaches targeting intracellular ROS levels have yielded mixed results. Since it is impossible to quant. detect dynamic ROS levels in tumors during and after chemotherapy in clin. settings, it is of increasing interest to apply math. modeling techniques to predict ROS levels for understanding complex tumor biol. during chemotherapy. This outlines the current understanding of the role of ROS in cancer cells during carcinogenesis and during chemotherapy, provides a crit. anal. of the methods used for quant. ROS detection and discusses the application of math. modeling in predicting treatment responses. Finally, we provide insights on and perspectives for future development of effective therapeutic ROS-inducing anticancer agents or antioxidants for cancer treatment.
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      McIlwain, D. R.; Berger, T.; Mak, T. W. Caspase Functions in Cell Death and Disease. Cold Spring Harbor Perspect. Biol. 2013, 5, a008656  DOI: 10.1101/cshperspect.a008656
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      Caspase functions in cell death and disease
      McIlwain, David R.; Berger, Thorsten; Mak, Tak W.
      Cold Spring Harbor Perspectives in Biology (2013), 5 (4), a008656/1-a008656/28CODEN: CSHPEU; ISSN:1943-0264. (Cold Spring Harbor Laboratory Press)
      A review. Caspases are a family of endoproteases that provide crit. links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their prodn. as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromol. complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the prodn. of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.
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    55. 55
      Roy, S.; Bhattacharya, K.; Mandal, C.; Dasgupta, A. K. Cellular Response to Chirality and Amplified Chirality. J. Mater. Chem. B 2013, 1, 6634– 6643,  DOI: 10.1039/c3tb21322f
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      Cellular response to chirality and amplified chirality
      Roy, Sarita; Bhattacharya, Kaushik; Mandal, Chitra; Dasgupta, Anjan Kr.
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (48), 6634-6643CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      In this paper we have explored how cancer cell line U87MG responds to drug penicillamine (PA) with reciprocal enantiomeric identities (i.e.l, d-forms). As nano-conjugation leads to amplification of chirality, cellular response to resp. chiral forms is studied in the presence and absence of nano-conjugation. The L,D-forms of the drug (penicillamine) and their silver nanoparticle conjugated forms are used and characterized by CD and fourier transform IR spectroscopy. The authors report that cells discriminate between the chiral forms through various mechanisms e.g. by altering mitochondrial membrane potential and selected elements of the caspase pathway. The striking feature which the authors would like to report is that chirality and the amplified chirality induced reciprocal responses may be dissimilar and even reciprocal. The work shows that the cellular response to geometrical chirality is an evolved concept and an amplified chirality by processes like nano-conjugation may be translated into an altered message in the cell.
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    56. 56
      Bhattacharya, K.; Samanta, S. K.; Tripathi, R.; Mallick, A.; Chandra, S.; Pal, B. C.; Shaha, C.; Mandal, C. Apoptotic Effects of Mahanine on Human Leukemic Cells are Mediated Through Crosstalk Between Apo-1/Fas Signaling and the Bid Protein and via Mitochondrial Pathways. Biochem. Pharmacol. 2010, 79, 361– 372,  DOI: 10.1016/j.bcp.2009.09.007
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      Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways
      Bhattacharya, Kaushik; Samanta, Suman K.; Tripathi, Rakshamani; Mallick, Asish; Chandra, Sarmila; Pal, Bikas C.; Shaha, Chandrima; Mandal, Chitra
      Biochemical Pharmacology (2010), 79 (3), 361-372CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
      Apo-1 (Fas/CD95), a cell surface receptor, triggers apoptosis after binding to its physiol. ligand, Apo-1L (FasL/CD95L). This study reports that mahanine, purified from the leaves of Murraya koenigii, has a dose- and time-dependent anti-proliferative activity in acute lymphoid (MOLT-3) and chronic myeloid (K562) leukemic cell lines and in the primary cells of leukemic and myeloid patients, with minimal effect on normal immune cells including CD34+ cells. Leukemic cells underwent phosphatidylserine externalization and DNA fragmentation, indicating mahanine-induced apoptosis. An increase in reactive oxygen species suggests that the mahanine-induced apoptosis was mediated by oxidative stress. A significant drop in the Bcl2/Bax ratio, the loss of mitochondrial transmembrane potential as well as cytochrome c release from the mitochondria to the cytosol suggested involvement of the mitochondrial pathway of apoptosis. Cytochrome c release was followed by the activation of caspase-9, caspase-3 and caspase-7, and cleavage of PARP in both MOLT-3 and K562 cells. In MOLT-3 cells, formation of the Fas-FasL-FADD-caspase-8 heterotetramer occurred, leading to the cleavage of Bid to its truncated form, which consequently resulted in formation of the mitochondrial transmembrane pore. The incubation of MOLT-3 cells with mahanine in the presence of caspase-8 inhibitor or FasL-neutralizing NOK-2 antibody resulted in the decrease of mahanine-induced cell death. Mahanine was also a potent inhibitor of K562 xenograft growth, which was evident in an athymic nude mice model. In summary, these results provide evidence for involvement of the death receptor-mediated extrinsic pathway of apoptosis in the mahanine-induced anticancer activity in MOLT-3 cells, but not in K562 cells, which are deficient in Fas/FasL.
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    57. 57
      Echeverria, P. C.; Bhattacharya, K.; Joshi, A.; Wang, T.; Picard, D. The Sensitivity to Hsp90 Inhibitors of Both Normal and Oncogenically Transformed Cells is Determined by the Equilibrium Between Cellular Quiescence and Activity. PLoS One 2019, 14, e0208287  DOI: 10.1371/journal.pone.0208287
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      The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity
      Echeverria, Pablo C.; Bhattacharya, Kaushik; Joshi, Abhinav; Wang, Tai; Picard, Didier
      PLoS One (2019), 14 (2), e0208287CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The mol. chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large no. of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clin. trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal vs. cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic anal. of the impact of three chem. different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metab. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.
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    58. 58
      Lanzetti, L.; Di Fiore, P. P. Endocytosis and Cancer: an ‘Insider’ Network with Dangerous Liaisons. Traffic 2008, 9, 2011– 2021,  DOI: 10.1111/j.1600-0854.2008.00816.x
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      Endocytosis and cancer: an 'insider' network with dangerous liaisons
      Lanzetti, Letizia; Di Fiore, Pier Paolo
      Traffic (Oxford, United Kingdom) (2008), 9 (12), 2011-2021CODEN: TRAFFA; ISSN:1398-9219. (Wiley-Blackwell)
      A review. From the signaling point of view, endocytosis has long been regarded as a major mechanism of attenuation, through the degrdn. of signaling receptors and, in some cases, of their ligands. This outlook has changed, over the past decade, as it has become clear that signaling persists in the endocytic route, and that intracellular endocytic stations (the 'signaling endosomes') actually contribute to the sorting of signals in space and time. Endocytosis-mediated recycling of receptors and of signaling mols. to specific regions of the plasma membrane is also coming into focus as a major mechanism in the execution of spatially restricted functions, such as cell motility. In addn., emerging evidence connects endocytosis as a whole, or individual endocytic proteins, to complex cellular programs, such as the control of the cell cycle, mitosis, apoptosis and cell fate detn. Thus, endocytosis seems to be deeply ingrained into the cell regulation blueprint and its subversion is predicted to play an important role in human diseases: first and foremost, cancer.
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    59. 59
      Faklaris, O.; Joshi, V.; Irinopoulou, T.; Tauc, P.; Sennour, M.; Girard, H.; Gesset, C.; Arnault, J.-C.; Thorel, A.; Boudou, J.-P.; Curmi, P. A.; Treussart, F. Photoluminescent Diamond Nanoparticles for Cell Labeling: Study of the Uptake Mechanism in Mammalian Cells. ACS Nano 2009, 3, 3955– 3962,  DOI: 10.1021/nn901014j
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      Photoluminescent Diamond Nanoparticles for Cell Labeling: Study of the Uptake Mechanism in Mammalian Cells
      Faklaris, Orestis; Joshi, Vandana; Irinopoulou, Theano; Tauc, Patrick; Sennour, Mohamed; Girard, Hugues; Gesset, Celine; Arnault, Jean-Charles; Thorel, Alain; Boudou, Jean-Paul; Curmi, Patrick A.; Treussart, Francois
      ACS Nano (2009), 3 (12), 3955-3962CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Diamond nanoparticles (nanodiamonds) have been recently proposed as new labels for cellular imaging. For small nanodiamonds (size <40 nm), resonant laser scattering and Raman scattering cross sections are too small to allow single nanoparticle observation. Nanodiamonds can, however, be rendered photoluminescent with a perfect photostability at room temp. Such a remarkable property allows easier single-particle tracking over long time scales. In this work, the authors use photoluminescent nanodiamonds of size <50 nm for intracellular labeling and investigate the mechanism of their uptake by living cells. By blocking selectively different uptake processes, the authors show that nanodiamonds enter cells mainly by endocytosis, and converging data indicate that it is clathrin-mediated. The authors also examine nanodiamond intracellular localization in endocytic vesicles using immunofluorescence and TEM. The authors find a high degree of colocalization between vesicles and the biggest nanoparticles or aggregates, while the smallest particles appear free in the cytosol. The authors' results pave the way for the use of photoluminescent nanodiamonds in targeted intracellular labeling or biomol. delivery.
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      Jiang, X.; Röcker, C.; Hafner, M.; Brandholt, S.; Dörlich, R. M.; Nienhaus, G. U. Endo- and Exocytosis of Zwitterionic Quantum Dot Nanoparticles by Live HeLa Cells. ACS Nano 2010, 4, 6787– 6797,  DOI: 10.1021/nn101277w
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      Endo- and Exocytosis of Zwitterionic Quantum Dot Nanoparticles by Live HeLa Cells
      Jiang, Xi-Ue; Roecker, Carlheinz; Hafner, Margit; Brandholt, Stefan; Doerlich, Rene M.; Nienhaus, G. Ulrich
      ACS Nano (2010), 4 (11), 6787-6797CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Uptake and intracellular transport of D-penicillamine coated quantum dots (DPA-QDs) of 4 nm radius by live HeLa cells have been investigated systematically by spinning disk and 4Pi confocal microscopies. Unlike larger nanoparticles, these small DPA-QDs were obsd. to accumulate at the plasma membrane prior to internalization, and the uptake efficiency scaled nonlinearly with the nanoparticle concn. Both observations indicate that a crit. threshold d. has to be exceeded for triggering the internalization process. By using specific inhibitors, we showed that DPA-QDs were predominantly internalized by clathrin-mediated endocytosis and to a smaller extent by macropinocytosis. Clusters of DPA-QDs were found in endosomes, which were actively transported along microtubules toward the perinuclear region. Later on, a significant fraction of endocytosed DPA-QDs were found in lysosomes, while others were actively transported to the cell periphery and exocytosed with a half-life of 21 min.
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      Zhao, J.; Stenzel, M. H. Entry of Nanoparticles into Cells: The Importance of Nanoparticle Properties. Polym. Chem. 2018, 9, 259– 272,  DOI: 10.1039/C7PY01603D
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      Entry of nanoparticles into cells: the importance of nanoparticle properties
      Zhao, Jiacheng; Stenzel, Martina H.
      Polymer Chemistry (2018), 9 (3), 259-272CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Knowledge of the interactions between nanoparticles (NPs) and cell membranes is of great importance for the design of safe and efficient nanomedicines. Extensive studies aimed at understanding the correlation of NP properties with endocytosis have been carried out in the past few years. Here, we review the recent progress of these studies and provide an overview of the current state of knowledge on the influence of NP size, shape, stiffness and surface chem. on cellular uptake. Special attention was dedicated to the uptake of non-spherical nanoparticles. Some general principles obtained from these fundamental studies will serve as guidelines for the design of optimized NP for enhanced cellular uptake. Finally, the opportunities for polymer chemists are discussed.
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      Fielding, A. B.; Willox, A. K.; Okeke, E.; Royle, S. J. Clathrin-Mediated Endocytosis is Inhibited During Mitosis. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 6572,  DOI: 10.1073/pnas.1117401109
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      Clathrin-mediated endocytosis is inhibited during mitosis
      Fielding, Andrew B.; Willox, Anna K.; Okeke, Emmanuel; Royle, Stephen J.
      Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (17), 6572-6577, S6572/1-S6572/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      A long-standing paradigm in cell biol. is the shutdown of endocytosis during mitosis. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase. A recent study proposed that endocytosis is continuous throughout the cell cycle and that the obsd. inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, and not to a shutdown of endocytosis. This challenge to the established view is gradually becoming accepted. Because of this controversy, we revisited the question of endocytic activity during mitosis. Using an antibody uptake assay and controlling for potential changes in surface receptor d., we demonstrate the strong inhibition of endocytosis in mitosis of CD8 chimeras contg. any of the three major internalization motifs for clathrin-mediated endocytosis (YXXΦ, [DE]XXXL[LI], or FXNPXY) or a CD8 protein with the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. The shutdown is not gradual: We describe a binary switch from endocytosis being "on" in interphase to "off" in mitosis as cells traverse the G2/M checkpoint. In addn., we show that the inhibition of transferrin uptake in mitosis occurs despite abundant transferrin receptor at the surface of HeLa cells. Our study finds no support for the recent idea that endocytosis continues during mitosis, and we conclude that endocytosis is temporarily shutdown during early mitosis.
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      Schweitzer, J. K.; Burke, E. E.; Goodson, H. V.; D’Souza-Schorey, C. Endocytosis Resumes during Late Mitosis and Is Required for Cytokinesis. J. Biol. Chem. 2005, 280, 41628– 41635,  DOI: 10.1074/jbc.M504497200
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      Endocytosis Resumes during Late Mitosis and Is Required for Cytokinesis
      Schweitzer, Jill Kuglin; Burke, Erin E.; Goodson, Holly V.; D'Souza-Schorey, Crislyn
      Journal of Biological Chemistry (2005), 280 (50), 41628-41635CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Recent work has underscored the importance of membrane trafficking events during cytokinesis. For example, targeted membrane secretion occurs at the cleavage furrow in animal cells, and proteins that regulate endocytosis also influence the process of cytokinesis. Nonetheless, the prevailing dogma is that endosomal membrane trafficking ceases during mitosis and resumes after cell division is complete. In this study, we have characterized endocytic membrane trafficking events that occur during mammalian cell cytokinesis. We have found that, although endocytosis ceases during the early stages of mitosis, it resumes during late mitosis in a temporally and spatially regulated pattern as cells progress from anaphase to cytokinesis. Using fixed and live cell imaging, we have found that, during cleavage furrow ingression, vesicles are internalized from the polar region and subsequently trafficked to the midbody area during later stages of cytokinesis. In addn., we have demonstrated that cytokinesis is inhibited when clathrin-mediated endocytosis is blocked using a series of dominant neg. mutants. In contrast to previous thought, we conclude that endocytosis resumes during the later stages of mitosis, before cytokinesis is completed. Furthermore, based on our findings, we propose that the proper regulation of endosomal membrane traffic is necessary for the successful completion of cytokinesis.
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      Zheng, K.; Xie, J. Engineering Ultrasmall Metal Nanoclusters as Promising Theranostic Agents. Trends Chem. 2020, 2, 665– 679,  DOI: 10.1016/j.trechm.2020.04.011
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      Engineering Ultrasmall Metal Nanoclusters as Promising Theranostic Agents
      Zheng, Kaiyuan; Xie, Jianping
      Trends in Chemistry (2020), 2 (7), 665-679CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)
      A review. Metal nanoclusters (NCs) are ultrasmall nanoparticles with intriguing mol.-like physicochem. properties. In recent years, metal NCs have been used as theranostic agents in biomedicine. In this short review, we correlate the physicochem. properties of metal NCs to their biomedical applications, shedding some light on the design of metal NC-based theranostic agents in cancer therapy, imaging-guided therapy, antimicrobial agents, and bioimaging. Such design principles could be readily realized in atomically precise metal NCs, leveraging recent advances in synthetic chem. and the structural resoln. of metal NCs.
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      Dejonghe, W.; Kuenen, S.; Mylle, E.; Vasileva, M.; Keech, O.; Viotti, C.; Swerts, J.; Fendrych, M.; Ortiz-Morea, F. A.; Mishev, K.; Delang, S.; Scholl, S.; Zarza, X.; Heilmann, M.; Kourelis, J.; Kasprowicz, J.; Nguyen, L. S. L.; Drozdzecki, A.; Van Houtte, I.; Szatmári, A.-M.; Majda, M.; Baisa, G.; Bednarek, S. Y.; Robert, S.; Audenaert, D.; Testerink, C.; Munnik, T.; Van Damme, D.; Heilmann, I.; Schumacher, K.; Winne, J.; Friml, J.; Verstreken, P.; Russinova, E. Mitochondrial Uncouplers Inhibit Clathrin-Mediated Endocytosis Largely Through Cytoplasmic Acidification. Nat. Commun. 2016, 7, 11710,  DOI: 10.1038/ncomms11710
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      Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification
      Dejonghe, Wim; Kuenen, Sabine; Mylle, Evelien; Vasileva, Mina; Keech, Olivier; Viotti, Corrado; Swerts, Jef; Fendrych, Matyas; Ortiz-Morea, Fausto Andres; Mishev, Kiril; Delang, Simon; Scholl, Stefan; Zarza, Xavier; Heilmann, Mareike; Kourelis, Jiorgos; Kasprowicz, Jaroslaw; Nguyen, Le Son Long; Drozdzecki, Andrzej; Van Houtte, Isabelle; Szatmari, Anna-Maria; Majda, Mateusz; Baisa, Gary; Bednarek, Sebastian York; Robert, Stephanie; Audenaert, Dominique; Testerink, Christa; Munnik, Teun; Van Damme, Daniel; Heilmann, Ingo; Schumacher, Karin; Winne, Johan; Friml, Jiri; Verstreken, Patrik; Russinova, Eugenia
      Nature Communications (2016), 7 (), 11710CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      ATP prodn. requires the establishment of an electrochem. proton gradient across the inner mitochondrial membrane. Mitochondrial uncouplers dissipate this proton gradient and disrupt numerous cellular processes, including vesicular trafficking, mainly through energy depletion. Here we show that Endosidin9 (ES9), a novel mitochondrial uncoupler, is a potent inhibitor of clathrin-mediated endocytosis (CME) in different systems and that ES9 induces inhibition of CME not because of its effect on cellular ATP, but rather due to its protonophore activity that leads to cytoplasm acidification. We show that the known tyrosine kinase inhibitor tyrphostinA23, which is routinely used to block CME, displays similar properties, thus questioning its use as a specific inhibitor of cargo recognition by the AP-2 adaptor complex via tyrosine motif-based endocytosis signals. Furthermore, we show that cytoplasm acidification dramatically affects the dynamics and recruitment of clathrin and assocd. adaptors, and leads to redn. of phosphatidylinositol 4,5-biphosphate from the plasma membrane.
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      Engelberg, S.; Modrejewski, J.; Walter, J. G.; Livney, Y. D.; Assaraf, Y. G. Cancer Cell-Selective, Clathrin-Mediated Endocytosis of Aptamer Decorated Nanoparticles. Oncotarget 2018, 9, 20993– 21006,  DOI: 10.18632/oncotarget.24772
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      Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles
      Engelberg Shira; Livney Yoav D; Modrejewski Julia; Walter Johanna G; Assaraf Yehuda G
      Oncotarget (2018), 9 (30), 20993-21006 ISSN:.
      Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (Kd = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance.
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      Bonora, M.; Patergnani, S.; Rimessi, A.; De Marchi, E.; Suski, J. M.; Bononi, A.; Giorgi, C.; Marchi, S.; Missiroli, S.; Poletti, F.; Wieckowski, M. R.; Pinton, P. ATP Synthesis and Storage. Purinergic Signalling 2012, 8, 343– 357,  DOI: 10.1007/s11302-012-9305-8
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      ATP synthesis and storage
      Bonora, Massimo; Patergnani, Simone; Rimessi, Alessandro; Marchi, Elena; Suski, Jan M.; Bononi, Angela; Giorgi, Carlotta; Marchi, Saverio; Missiroli, Sonia; Poletti, Federica; Wieckowski, Mariusz R.; Pinton, Paolo
      Purinergic Signalling (2012), 8 (3), 343-357CODEN: PSUIA9; ISSN:1573-9538. (Springer)
      A review. Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metab. revolve around ATP prodn. and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amt. of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signaling mol. in the purinergic signaling mechanisms. In this review, the authors will discuss all the main mechanisms of ATP prodn. linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signaling events. Recent advances regarding ATP storage and its special significance for purinergic signaling will also be reviewed.
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      Moro, L. Mitochondrial Dysfunction in Aging and Cancer. J. Clin. Med. 2019, 8, 1983,  DOI: 10.3390/jcm8111983
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      Mitochondrial dysfunction in aging and cancer
      Moro, Loredana
      Journal of Clinical Medicine (2019), 8 (11), 1983CODEN: JCMOHK; ISSN:2077-0383. (MDPI AG)
      Aging is a major risk factor for developing cancer, suggesting that these two events may represent two sides of the same coin. It is becoming clear that some mechanisms involved in the aging process are shared with tumorigenesis, through convergent or divergent pathways. Increasing evidence supports a role for mitochondrial dysfunction in promoting aging and in supporting tumorigenesis and cancer progression to a metastatic phenotype. Here, a summary of the current knowledge of three aspects of mitochondrial biol. that link mitochondria to aging and cancer is presented. In particular, the focus is on mutations and changes in content of the mitochondrial genome, activation of mitochondria-to-nucleus signaling and the newly discovered mitochondria-telomere communication.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsl2gt78%253D&md5=7bbbb10ad3c15cfea40ee40c7bc9baee
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