logo

Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Omega 2019, 4, 5, 8094-8103
RETURN TO ISSUEPREVArticleNEXT

Cytotoxic Activity of Royleanone Diterpenes from Plectranthus madagascariensis Benth

  • Diogo Matias
    Diogo Matias
    Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
    Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcalá, Campus Universitario, 28871 Alcalá de Henares, Spain
    More by Diogo Matias
    • , 
  • Marisa Nicolai
    Marisa Nicolai
    Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
    More by Marisa Nicolai
    • , 
  • Lucília Saraiva
    Lucília Saraiva
    LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
    More by Lucília Saraiva
    Orcidhttp://orcid.org/0000-0002-9531-4939
    • , 
  • Rute Pinheiro
    Rute Pinheiro
    LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
    More by Rute Pinheiro
    • , 
  • Célia Faustino
    Célia Faustino
    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal
    More by Célia Faustino
    • , 
  • Ana Diaz Lanza
    Ana Diaz Lanza
    Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcalá, Campus Universitario, 28871 Alcalá de Henares, Spain
    More by Ana Diaz Lanza
    • , 
  • Catarina Pinto Reis
    Catarina Pinto Reis
    Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal
    More by Catarina Pinto Reis
    • , 
  • Tijana Stankovic
    Tijana Stankovic
    Institute for Biological Research “Siniša Stanković”, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia
    More by Tijana Stankovic
    • , 
  • Jelena Dinic
    Jelena Dinic
    Institute for Biological Research “Siniša Stanković”, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia
    More by Jelena Dinic
    • , 
  • Milica Pesic
    Milica Pesic
    Institute for Biological Research “Siniša Stanković”, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia
    More by Milica Pesic
    Orcidhttp://orcid.org/0000-0002-9045-8239
    • , and 
  • Patrícia Rijo*
    Patrícia Rijo
    Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal
    *E-mail: [email protected]. Tel: 351 21 7515577. Fax: 351 21 7515598.
    More by Patrícia Rijo
    Orcidhttp://orcid.org/0000-0001-7992-8343
Cite this: ACS Omega 2019, 4, 5, 8094–8103
Publication Date (Web):May 2, 2019
https://doi.org/10.1021/acsomega.9b00512
Copyright © 2019 American Chemical Society
RIGHTS & PERMISSIONS
Authors ChoiceACS AuthorChoice
Article Views
1184
Altmetric
-
Citations
2
LEARN ABOUT THESE METRICS

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

PDF (913 KB)
Supporting Info (1)»
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide

Cytotoxicity screenings have identified Plectranthus plants as potential sources of antitumor lead compounds. In this work, several extracts from Plectranthus madagascariensis were prepared using different solvents (acetone, methanol, and supercritical CO2) and extraction techniques (maceration, ultrasound-assisted, and supercritical fluid extraction), and their chemical composition was detailed using high-performance liquid chromatography with a diode array detector. The cytotoxic activity of the major compounds identified, namely, rosmarinic acid (1) and abietane diterpenes 7α,6β-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5), was evaluated in a battery of human cancer cell lines, including breast (MDA-MB-231, MCF-7), colon (HCT116), and lung (NCI-H460, NCI-H460/R) cancer, and also in healthy lung (MCR-5) cells. Royleanone (3) was isolated for the first time from P. madagascariensis, and its full spectroscopic characterization (proton and carbon nuclear magnetic resonance) was accomplished. A high selectivity for lung cancer cells was observed for royleanones (2, 4) with selectivity indexes of 4.3 and 3.2, respectively. The observed results combined with literature data allowed the establishment of important structure–activity relationships for substituted royleanone abietanes, such as the requirement for an electron-donating group at positions 6 and/or 7 in the abietane skeleton, and an improved cytotoxic effect for substituents with log P values between 2 and 5.

Introduction

ARTICLE SECTIONS
Jump To
Plectranthus species have been traditionally used for a wide range of complaints,(1) mainly of the respiratory system, gastrointestinal tract, nervous system, skin disorders, infections, pain, and different types of cancer due to their medicinal properties, which include antimicrobial,(2−5) antioxidant,(3,6) anti-inflammatory,(7,8) and cytotoxic(7−11) activities. Several cytotoxic activity studies have been performed on Plectranthus spp. Cytotoxicity screening of South African medicinal plants traditionally used in the treatment or prevention of cancer(12) revealed that the extracts of Plectranthus ciliatus and Plectranthus barbatus inhibited the growth of both sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Similarly, in another in vitro screening using the RBL-2H3 cell line,(8)P. ciliatus showed higher cytotoxicity among the acetone extracts of the seven Plectranthus species tested.
The organic extracts of Plectranthus amboinicus also exhibit relevant cytotoxicity. The ethyl acetate extract inhibited the growth of breast cancer MCF-7 cells,(13) whereas the ethanol extract suppressed growth and induced apoptosis in the human lung cancer A549 cell line.(14) Moreover, the hydroalcoholic extract from leaves of P. amboinicus showed interesting in vivo antitumor effects.(7) On the other hand, the ethanol extract from aerial parts of Plectranthus neochilus has shown cytotoxic effects in the Artemia salina model,(15) and more recently, a hexane extract showed growth inhibitory effects in cell carcinoma cell lines.(16)
The promising results from the screening of Plectranthus extracts followed by the bio-guided isolation of the active compounds led to the elucidation of some promising anticancer lead compounds, namely, labdane and abietane diterpenes. The labdane diterpene forskolin, isolated from the roots of P. barbatus, was one of the first compounds isolated from Plectranthus species with promising anticancer activity.(17) Furthermore, forskolin was shown to be a potent inhibitor of the growth of colon cancer cells with induction of cycle arrest at the G1 phase and further apoptosis.(18)
Abietane diterpenes of the royleanone and coleon type commonly found in the Plectranthus genus, as well as other abietanoid quinone methides, such as Parvifloron D isolated from Plectranthus ecklonii,(9) have been described as potent antiproliferative and/or cytotoxic agents.(9−11,19−21)
Previous cytotoxicity activity screening performed by our group from Plectranthus madagascariensis, P. neochilus, and Plectranthus porcatus revealed promising cytotoxic activity of the P. madagascariensis extract obtained by maceration in acetone and in the MDA-MB-231 breast cancer cell line,(24) encouraging further research. In this study, the chemical composition of several P. madagascariensis extracts obtained using different organic solvents and extraction methodologies was detailed using high-performance liquid chromatography with a diode array detector (HPLC-DAD) and complementary spectroscopic methodologies, and the major compounds were identified and quantified. The cytotoxic effects of the pure compounds were evaluated in human breast, lung, and colon cancer cell lines, and relevant structure–activity relationships were disclosed for the royleanone-type abietane diterpenes.

Results and Discussion

ARTICLE SECTIONS
Jump To

Preparation of P. madagascariensis Extracts

Several extracts from P. madagascariensis have been prepared using different solvents (acetone, methanol, and supercritical CO2) and extraction techniques (maceration, ultrasound-assisted, and supercritical fluid extraction), resulting in different extractive yields (Table 1).
Table 1. Preparation, Yields, and Component Quantification of P. madagascariensis Extracts
    component yield in extract (mg/g)b
extractsolventmethodaextraction yield (mg/g)(1)(2)(3)(4)(5)
E1acetoneUAE1.5129.84.621.641.0415.5
E2acetoneME1.4517.53.196.741.215.77
E3methanolUAE6.564.604.200.810.77t
E4methanolME12.026.41.050.24tt
E5scCO2SCFE1.3117.84.980.200.84n/d
E6acetoneR-SCFE2.9550.50.330.17n/dn/d
a

UAE, ultrasound-assisted extraction; ME, maceration extraction; SCFE, supercritical fluid extraction; R-SCFE, re-extraction of SCFE remaining plant material.

b

t, traces. n/d not detected. The extraction yield is express in mg of extract per g of plant dry material. The component yield is express in mg of component per g of plant dry material.

Higher extractive yields were obtained using methanol as the solvent, which can be due to the ability of alcohol to disrupt the plant cell wall favoring the diffusion of secondary metabolites to the bulk extract. Moreover, considering the relative polarity of the extraction solvents in terms of dielectric constant (ε), a trend was observed for the more polar solvents to achieve higher extraction yields (εmethanol > εacetone ≫ εscCO2). The supercritical fluid extraction (SCFE) method using scCO2 was the least efficient extraction process with the lower yield. Because of this low extraction efficiency, a re-extraction of the remaining plant material with acetone was performed to extract the remaining secondary metabolites, which resulted in a higher extraction yield (E6, Table 1) when compared to SCFE alone.

HPLC-DAD Extract Profiling

The identification and quantification of major compounds (rosmarinic acid (1), 6β,7α-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5); Figure 1) in P. madagascariensis extracts were performed using HPLC-DAD and complementary spectroscopic methodologies.

Figure 1

Figure 1. Chemical structure of the major components in P. madagascariensis extracts: rosmarinic acid (1), 6β,7α-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5).

High Resolution Image
Download MS PowerPoint Slide
Previous phytochemistry studies on the Plectranthus genus revealed the presence of polyphenols and diterpenes as the most frequent secondary metabolites.(3,6,32) These compounds have characteristic absorption patterns in the UV spectral region due to the presence of conjugated carbonyl groups (270 nm), aromatic rings (280 nm), and phenolic groups (330 nm); thus, analytical measurements were performed at these three wavelengths. HPLC representative chromatograms of P. madagascariensis extracts are available at the Supporting Information (Figure S1). For each extract, the major peaks were identified by comparing the retention time and UV–vis spectrum overlay (Figure S2, Supporting Information) by co-elution with pure standards. The peak eluted at 10.47 min, which was present in all extracts, was positively identified as rosmarinic acid (1, Figure 1) after co-elution with a commercial standard (Figure S2, Supporting Information). This polyphenol, found in several Plectranthus species, had been previously identified in P. madagascariensis.(5,33)
The peaks obtained at the average retention times of 17.80, 19.40, and 19.80 min possessed the typical royleanone-type abietane UV spectra(25) (Figure S1, Supporting Information) with an absorption maximum at 272 nm and a secondary broad maximum between 300 and 500 nm, in accordance with other phytochemical studies of Plectranthus species.(32) The peaks at 17.80 and 19.80 min were identified as 6β,7α-dihydroxyroyleanone (2, Figure 1) and 7α-acetoxy-6β-hydroxyroyleanone (4, Figure 1), respectively, after co-elution of the extracts with authentic samples previously obtained from Plectranthus spp.(2) The peak at 19.40 min was identified as 7α-formyloxy-6β-hydroxyroyleanone (3, Figure 1), isolated from the acetone extract prepared by UAE, after co-elution with the purified compound. A major peak eluted at 21.08 min showing a UV spectrum (Figure S1, Supporting Information) comparable to that of coleon U (5, Figure 1),(23) a diterpene often found in Plectranthus species, which was confirmed after co-elution of the extracts with an authentic sample.(2) This compound was reported to have some intrinsic instability, being easily converted to an oxidized form, coleon U-quinone (6, Figure 2).(23,25) This degradation product was also detected in some P. madagascariensis extracts as a trace at a retention time of 19.19 min. The periodic analysis of an authentic sample of (5) revealed the gradual increase of the peak at 19.19 min and concomitant reduction of the peak at 21.08 min, which represents a gradual conversion of the compound (5) into its oxidized form (6, Figure 2).

Figure 2

Figure 2. HPLC chromatogram showing the decomposition of coleon U (5) to coleon U quinone (6).

High Resolution Image
Download MS PowerPoint Slide

Isolation and Spectroscopic Structure Elucidation of 7α-Formyloxy-6β-hydroxyroyleanone (3)

The compound (3) was isolated from the acetone extract of P. madagascariensis (480 mg of dried residue) prepared by UAE following column chromatography using hexane/ethyl acetate 95:5 (v/v) as an eluent and purified using preparative chromatography through repeated elution with hexane/ethyl acetate 75:25 (v/v), yielding 6.1 mg (1.27% (w/w) yield) of yellow needles after recrystallization from methanol. The compound was fully characterized using NMR spectroscopy (1H and 13C NMR spectra available in the Supporting Information, Figures S3 and S4, respectively).
The 1H NMR spectrum of (3) (Figure S3, Supporting Information) was very similar to that of royleanone (4).(29) The main differences were due to the absence of the singlet signal at δ 2.02 ppm corresponding to the methyl protons of the acetoxyl group at C7 in (4) and the presence of a distinct doublet at δ 8.05 ppm (J = 1.2 Hz), which might correspond to an acidic proton from a secondary formyloxyl group.(30) This observation suggested the substitution of the 7α-acetoxyl group of (4) by 7α-formyloxyl in (3), which was confirmed by the literature(30) and extensive NMR studies (1H and 13C NMR, COSY, HMBC, and HMQC; Table 2). Thus, the compound (3) was identified as 7α-formyloxy-6β-hydroxyroyleanone, which has been previously isolated from Plectranthus hadiensis(31) and Plectranthus myrianthus.(25) To our knowledge, this was the first isolation of (3) from P. madagascariensis and its first full 13C NMR characterization.
Table 2. NMR Spectroscopic Data (400 MHz, CDCl3) for 7α-Formyloxy-6β-hydroxyroyleanone (3)
positionδC, typeδH (J in Hz)HMBC
138.49, CH21.19, s; 2.64, d (12.9) 
219.09, CH21.50, m; 1.85, d (4.5) 
342.45, CH21.20, 1.50, m 
433.83, C  
549.80, CH1.38, s10
6α67.25, CH4.37, m 
7β68.42, CH5.80, m 
8136.45, C  
9150.38, C  
1038.79, C  
11183.34, C  
12151.13, C  
13124.35, C  
14183.34, C  
1524.34, CH3.17, qi (14.1; 7.1)13
1633.85, CH31.24, d (7.1) 
1720.01, CH31.21, d (7.1)13
1833.57, CH30.96, s3, 5, 19
1923.97, CH31.25, s3, 5, 18
2021.71, CH31.62, s1, 5
21159.64, CH8.04, d (1.2) 
6-OH (1) 2.31, t (7.5) 
12-OH (2) 7.20, m (3.1) 
Kubínová et al.(5) have studied the methanol extract of P. madagascariensis, which resulted in the identification of rosmarinic acid (1), 6β,7α-dihydroxyroyleanone (2), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U-quinone (6) as the major components of this extract. However, the full spectroscopic elucidation of these compounds was not accomplished by the authors.
The quantification of the major compounds in P. madagascariensis extracts was also performed based on the validated calibration curves for main polyphenol rosmarinic acid (1) and main abietane diterpenes 6β,7α-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5). Linear responses and high sensitivity were obtained for all compounds (Table S1, Supporting Information). The component yield in each extract has been listed in Table 1.
7α-acetoxy-6β-hydroxyroyleanone (4) obtained from Plectranthus grandidentatus is described to show strong in vitro antiproliferative activity against several human cancer cell lines,(11) whereas taxodione from P. barbatus and their semisynthetic derivatives were highly cytotoxic toward human leukemia cells.(19) Growth inhibition triggered by these compounds was caused by induction of apoptosis, whereas cell death was associated with the release of mitochondrial proteins due to mitochondrial membrane depolarization.(19) Additionally, 7α-acetoxy-6β-hydroxyroyleanone (4) was identified as the main compound that contributed to the cytotoxic activity of the chloroform extract of P. amboinicus against breast cancer MCF-7 cells, using an HPLC-based metabolomics approach.(22)
Rosmarinic acid (1) was the most abundant secondary metabolite present in all extracts, with yields ranging from 4.60 to 50.5 mg/g (Table 1). This finding is in agreement with the described abundance of this polyphenol in other Plectranthus species.(6,32) Coleon U (5) was diterpene quantified in higher yields, although high yields of royleanone-type diterpenes (2–4) were also found in all extracts, particularly in the acetone ones (E1 and E2, Table 1).
Coleon U has been isolated from several Plectranthus species, such as Plectranthus forsteri,(23)P. grandidentatus,(10,11)P. madagascariensis(24) and P. myrianthus,(25) exhibits potent cytotoxic effects transversal to several human cancer cell lines, including breast,(11,19) lung,(11) leukemia,(10,19,26) and melanoma.(11,19) Moreover, coleon U has been described as a potent and selective activator of the proapoptotic protein kinases C-δ (PKCδ) and C-ε (PKCε), which can be on the basis of its reported antitumor action.(27,28) However, coleon U is easily degraded to its oxidized form, coleon U-quinone. This metabolite has been isolated from Plectranthus xanthanthus along with coleon U 11-acetate, and both showed cytotoxic effects.(23,26)

Cytotoxicity Evaluation

The cytotoxic effects of P. madagascariensis extracts have been previously evaluated in the MDA-MB-231 cancer cell line by our group,(24) and the isolated abietane diterpenes most likely contribute to the cytotoxicity of P. madagascariensis extracts. The extract obtained by maceration with acetone (E2), which had the highest combinatory yield of royleanone abietanes (Table 1), was the most cytotoxic.(24) The cytotoxic activities of the royleanone diterpenes, that is, against breast cancer cell lines, have been previously reported.(11,19) Additionally, coleon U (5) has been described in the literature as a potent cytotoxic agent, being active against breast,(11,19) leukemia,(10,19,26) and melanoma(11,19) cancer cell lines. However, the acetone extract (E1) prepared by UAE and previously analyzed,(24) which had the highest yield of coleon U (5) and also the highest combinatory yield of abietane diterpenes, was not the most cytotoxic. This can be due to its higher amount of rosmarinic acid (1) because the most cytotoxic extract (E2) had a lower yield of this polyphenol compared to the other extracts (Table 1). Rosmarinic acid (1) is known to be a potent antioxidant,(6) and some studies related the cytotoxic effect of abietane diterpenes possessing conjugated quinone moieties to the induction of radical reactions,(20,21) which may anticipate a potential antagonistic effect between antioxidant polyphenols and conjugated quinone diterpenes.
The cytotoxic activity of isolated compounds (1–5) from P. madagascariensis extracts was assayed in breast cancer (MDA-MB-231 and MCF-7), colon cancer (HCT116), non-small cell lung cancer (NCI-H460), and normal lung bronchial (MCR-5) cell lines (Table 3). Interestingly, in the MCF-7 cell line, the structural modifications carried out in compounds (3–5) significantly increased their antiproliferative effects when compared to that in the compound 2 (Table 3). All abietane diterpenes revealed growth inhibitory effects in most of the cancer cell lines tested. Moreover, royleanones (2, 4) exhibited high selectivity based on the comparison of GI50 for cancer (NCI-H460) and normal lung (MCR-5) cell lines. These royleanones also showed similar growth inhibition of the NCI-H460 cancer cell line and its multidrug-resistant variant (NCI-H460/R), which overexpress the multidrug resistance protein 1 (MDR1 or P-glycoprotein),(34) suggesting that compounds (2, 4) are not substrates for such efflux pumps.
Table 3. Concentration of Major Compounds from P. madagascariensis Extracts Causing 50% Cell Growth Inhibition (GI50/μM) of Human Cell Linesa
 sulfurhodamine B (SRB) assayMTT assay 
 cell line 
compoundMDA-MB-231MCF-7HCT116NCI-H460NCI-H460/RMCR-5SI
(1)>100ntnt>100>100>100 
(2)>10026.0 ± 0.6≥5025 ± 225 ± 291 ± 134.3*
(3)>1007.9 ± 0.8§7.9 ± 1.214.9 ± 2.9ntnt 
(4)>1006.4 ± 0.4#§ 2.7 ± 0.43.1 ± 0.48.6 ± 0.43.2*
(5)46.95.5 ± 0.8#§ 3.0 ± 0.2#ntnt 
positive controlDOX 0.072 ± 0.0021DOX 0.16 ± 0.0018DOX 0.125 ± 0.0013PCX 0.0006 ± 0.0001PCX 0.117 ± 0.013PCX 0.523 ± 0.001PCX 872***
a

Selectivity index, SI = GI50(MCR-5)/GI50(NCI-H460). nt, not tested. #Previously reported results from our group.(11) Doxorubicin (DOX) was used as positive control in MDA-MB-231, MCF-7, and HCT116 cells. Paclitaxel (PCX) was used as positive control in NCI-H460, NCI-H460/R, and MCR-5 cells. Significant selectivity toward cancer cells: *p < 0.05, ***p < 0.001 (in NCI-H460, NCI-H460/R, and MCR-5 cells). §Values significantly different from compound (2), P < 0.05.

On the one hand, the growth of MDA-MB-231 cancer cells was not particularly affected by abietane diterpenes. This cell line is a highly metastatic triple negative breast cancer cell line that does not display estrogenic receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER2), thus being clinically difficult to target.(35) The ER negative cells are known to have a higher expression of PKC classic isoforms when compared to ER positive cell lines.(36) The upregulation of the classic isoform PKCα promotes the invasiveness and metastasis formation(36) along with increased drug resistance(37) in breast cancers. On the other hand, the PKCδ activation supports both prosurvival(38) and proapoptotic(39) functions in breast cancer cells. Some abietane diterpenes such as coleon U (5) have also been shown to exert proapoptotic effects by the specific activation of PKC-δ and PKC-ε.(27,28) Therefore, in the MDA-MB-231 cell line characterized by an overexpression of classic PKC isoforms in detriment of new PKC isoforms, the preferential mechanism of apoptosis induction by coleon U (and eventually by other abietane diterpenes) through activation of PKC-δ and PKC-ε should be less effective, which can explain the lower growth inhibition of this cell line by these compounds.
Some relationships between the PKC overexpression and the drug resistance by MDR1 have been reported. A cellular increase of the MDR1 expression was verified following the treatment with the PKC activator TPA, which was suppressed by the use of a PKC inhibitor (staurosporine).(40) Furthermore, the use of the PKC inhibitor, bryostatin 1, potentiated the cytotoxic effects of anticancer drugs transported by efflux pumps, such as vincristine, by the reduction of MDR1 expression.(41) Those findings can be especially relevant in the case of abietane diterpenes being not transported by MDR1 for which the PKC activation and the secondary MDR1 overexpression should not increase the cell resistance to such compounds.

Structure–Activity Relationships

The obtained data on abietane diterpene cytotoxicity (Table 3) combined with other studies on the cytotoxicity of this class of compounds (Table 4) allowed the establishment of some structure–activity relationships (SARs) for royleanone-type abietanes. The main difference between royleanones (2) and (4) resides on the polarity of the substituent at 7α (Figure 1). In this series, a clear tendency was observed for increasing cytotoxicity with the higher lipophilicity of the 7α substituent. The same tendency was observed between horminone (Figure 3, R1 = H, R2 = R3 = OH) and its more cytotoxic 7α-acetoxy derivative (Figure 3, R1 = H, R2 = OCOCH3, R3 = OH).(42,43) Whether these structural alterations corresponded to an improved fitting on the target or if the cytotoxic activity was instigated by favorable log P for membrane crossing remains to be answered because the cytotoxicity of several diterpenes has been associated with a mechanism involving membrane-disrupting properties.(3,44)

Figure 3

Figure 3. Proposed structure–activity relationships for 6,7,12-substituted royleanone-type abietane diterpenes based on data from Table 4.

High Resolution Image
Download MS PowerPoint Slide
Table 4. Cytotoxicity of Several Royleanone Derivatives against Different Cell Lines According to the Literaturea,b
    cell lines
compound featurescbreastCNScolongastricleukemia/lymphomamelanomapapillomapancreasrenallungnormalmelanoma
R1R2R3log PMCF-7(11,19)SF-268(11,19)HCT116(11,19)AGS(46)HL-60(47,48)P-388(49)U937(19)Molt-3(19)MEL-1(19)UACC-62(11)MV-3(42)KB(49)PaCa-2(42)TK-10(11)H460(46)MCR-5(46)
OHOHOH0.85+––      –   ––+
OHOCHOOH0.97++++++             
OHOCOCH3OH1.08++   + ++++++   +++++++
OCOCH3OCOCH3OH1.31+   + ++++       
OCOCH3OCOCH3OCOCH31.54++   ++ +++++++       
H=OOH1.57          – –   
HβOHOH1.74   –           +
HOHOH1.74   + +++    +++  +
OCOCH2CH3OCOCH3OH1.96+   + ++++++       
HOCOCH3OH1.97          ++ +++   
OHOCH3OH2.10     +++     +    
OHOCOCH3OCOPh(4-NO2)2.30+   ++ +++++++       
OCO(CH2)2CH3OCOCH3OH2.38++   ++ +++++++++       
HΔ(6,7)HΔ(6,7)OH2.51   –+++/++++     ++   +/–
HHOH2.83   –– –+– – –  +
OCOCH2CH3OCOCH3OCOCH2CH32.85+   +++ +++++       
OHOCOCH3OCOPh(4-CH3)3.69+++   +++ ++++++++       
OHOCOCH3OCOPh(4-Cl)3.77+++   +++ +++++++++       
OCOPh(4-NO2)OCOCH3OH4.31++   +++ ++++++++       
OCOPhOCOCH3OCOPh5.33+   +++ ++++++++       
OCOPh(4-Cl)OCOCH3OCOPh(4-Cl)6.45–   ++ ++––       
OHO-FAOH>7––       –   –– 
a

Unless otherwise stated, R2 conformation is β; FA, fatty acid; log P values estimated using ChemBioDraw; −, not active (GI50 > 30 μM); +, low cytotoxic (10 < GI50 ≤ 30 μM); ++, cytotoxic (5 < GI50 ≤ 10 μM); +++, highly cytotoxic (GI50 ≤ 5 μM); Ph, phenyl group.

b

References in square brackets.

c

See Figure 3 for chemical structure.

On the basis of the extensive literature reporting the cytotoxicity on royleanone-type compounds bearing a p-benzoquinone moiety in the ring C (Figure 3), additional tendencies could be explored (Table 4).
Burmistrova et al.(19) studied the cytotoxic effects for a series of derivatives of 7α-acetoxy-6β-hydroxyroyleanone (4). The overall compounds affect the cell proliferation with an apparently cell-type dependent intensity. By displaying such compounds by their log P value, a strong tendency for higher cytotoxic effects was observed for log P values between 2 and 5.5. Because the “Lipinski rule of five” establishes that log P for an oral bioavailable compound should be under 5, the useful compounds must be considered in the 2–5 range of log P.(45) The only exception for this trend was royleanone (Figure 3, R1 = R2 = H, R3 = OH) that showed only slight cytotoxic effects in some cell lines.(19,42,46) This could indicate that the presence of a lipophilic substituent was required at positions 6 and/or 7 for the cytotoxic effects to take place. However, the 6,7-dehydro derivative (Figure 3, R1 = R2 = HΔ,(6,7) R3 = OH) has shown some potent cell-type specific cytotoxic effects.(47−49) Thus, the presence of an electron-donating group at position 6 or 7 seems to be essential for cytotoxic activity.
The cytotoxicity of the studied abietane diterpenes against most of the cancer cell lines tested and the selectivity of the royleanone-type compounds, particularly for non-small lung cancer cells and their multidrug-resistant variant, encourage further studies using this scaffold to develop analogues with potential application as chemopreventive, chemoadjuvant, or chemotherapeutic agents.

Experimental Section

ARTICLE SECTIONS
Jump To

General Experimental Procedures

Chemical reagents and standards were from Sigma-Aldrich and used as received. Authentic samples of 7α,6β-dihydroxyroyleanone (2), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5) were obtained from Gaspar-Marques.(2) Solvents of either analytical or HPLC grade were from Merck. Fetal bovine serum (FBS) was from Gibco, penicillin–streptomycin for the cell culture and an RPMI 1640 culture medium with ultraglutamine were from Lonza, and Dulbecco’s modified Eagle’s medium (DMEM) was from Biowest. Analytical TLC and preparative TLC were performed on precoated silica gel plates from Merck (Kieselgel 60 F254, 0.2 and 0.5 mm). For column chromatography, silica gel 60 (0.063–0.200 mm) from Merck was used. NMR spectra were recorded on a Varian INOVA-400 spectrometer (Varian, Palo Alto, CA, USA) equipped with a 5 mm inverse detection z-gradient probe. The 1H and 13C NMR spectra were acquired at 400 and 100 MHz, respectively, using CDCl3 as the solvent, and the chemical shifts were reported in parts per million referring to the residual CHCl3 signal (δH 7.26 for proton and δC 77.0 for carbon).

Cell Cultures

The human cell lines MDA-MB-231 (metastatic breast cancer), MCF-7 (estrogen-dependent breast carcinoma), HCT116 (colorectal carcinoma), NCI-H460 (non-small cell lung carcinoma), and MCR-5 (normal human embryonal bronchial epithelial cells) were obtained from the American Type Culture Collection (ATCC, Rockville, MD). The multidrug-resistant non-small cell lung carcinoma cell line (NCI-H460/R) with P-glycoprotein overexpression was obtained from the original NCI-H460 cell line by continuous treatment with stepwise increasing concentrations of doxorubicin (5–100 nM) for 3 months according to a procedure optimized by Pesic et al.(34) Cell lines were routinely cultured in RPMI 1640 with ultraglutamine or DMEM (MDA-MB-231 cells), supplemented with 10% FBS, 100 U/mL penicillin, and 0.1 mg/mL streptomycin, and maintained under standard cell conditions at 37 °C under a humidified atmosphere containing 5% CO2.(50,51)

Plant Material

Plectranthus madagascarensis Benth. was cultivated in Parque Botânico da Tapada da Ajuda (Instituto Superior Agrário, Lisbon, Portugal) from cuttings obtained from the Kirstenbosch National Botanical Garden (Cape Town, South Africa), and voucher specimens (841/2007) were deposited in the Herbarium João de Carvalho e Vasconcellos (Instituto Superior Agrário, Lisbon, Portugal). The whole plant material was collected in 2007, dried at room temperature, and stored protected from light and humidity.

Extract Preparation

The dried plant was ground to small pieces, pulverized, and extracted with acetone or methanol by maceration (ME) or ultrasound-assisted extraction (UAE) and also by supercritical fluid extraction (SCFE) with supercritical CO2 (scCO2). Each crude extract was separated from the remaining plant material by paper filtration, and the organic solvents were evaporated in a rotary evaporator below 40 °C. Each dried extract was weighted and stored at −20 °C until further use.
The organic extracts were prepared by maceration (ME) or ultrasound-assisted (UAE) extraction by adding the plant material (10 g) to 200 mL of organic solvent (acetone or methanol) kept stirring for 24 h (ME) or sonicated in an ultrasonic bath at 35 kHz for 2 h (UAE). Alternatively, supercritical fluid extraction (SCFE) was also performed by packing the plant material (30 g) into a 278 cm3 inox cell and injecting scCO2 during 3 h at a flow rate of 0.3 kg/h under a pressure of 230 bar and a temperature of 40 °C.(52) The remaining plant material resulting from SCFE was recovered, air dried, and re-extracted (R-SCFE) by addition to 200 mL of acetone kept stirring for 24 h at room temperature.

Extraction and Purification of 7α-Formyloxy-6β-hydroxyroyleanone (3)

Ultrasound-assisted extraction of P. madagascariensis by sonication of 100 g of plant material in 2 L of acetone for 2 h yielded 480 mg of dried residue (0.48% (w/w) extraction yield) after evaporation of the organic solvent. The extract was treated with activated charcoal to eliminate the high content in chlorophyll plant pigments and fractionated by chromatography on a silica gel (30 g) column eluted with a gradient of ethyl acetate in hexane. The compound (3) was recovered from the fraction eluted with hexane/ethyl acetate 95:5 (v/v) and purified by preparative chromatography through repeated elution with hexane/ethyl acetate 75:25 (v/v) followed by recrystallization from methanol, yielding 6.1 mg (1.27% (w/w) yield) of yellow needles. Spectroscopic characterization was performed by one-dimensional (1H and 13C NMR) and two-dimensional (COSY, HMBC, and HSQC) NMR (Table 2 and Figures S3 and S4, Supporting Information).

HPLC-DAD Fingerprinting

The extract profiling was performed with an Agilent Technologies 1200 Infinity Series LC system (Agilent Technologies, Santa Clara, CA, USA) coupled to a diode array detector (DAD) and processed using the ChemStation software. Four detection wavelengths were selected: 254, 270, 280, and 330 nm. A 20 μL sample was injected into a reverse phase LiChrospher 100 RP-18 5 μm (4.0 × 250 mm) column (Merck, Darmstadt, Germany) and eluted with a gradient composed of methanol (A), acetonitrile (B), and 0.3% (w/v) trichloroacetic acid in ultrapure water (C) as follows: 0 min, 15% A, 5% B, and 80% C; 20 min, 70% A, 30% B, and 0% C; 25 min, 70% A, 30% B, and 0% C; and 28 min, 15% A, 5% B, and 80% C. The flow rate was set at 1 mL/min at room temperature. Solvents were previously filtered and degassed through a 0.22 μm membrane filter. All analysis was performed in triplicate, and the results are presented as mean ± SD.
The major peaks from each extract sample were identified by comparing the retention time and UV–vis spectrum overlay with commercial standards (rosmarinic acid) or authentic standards previously obtained from Plectranthus spp.(2) The calibration curves were constructed as a linear regression of the analyte concentration (mM) against the average peak area. The limit of detection (LOD) and limit of quantification (LOQ) were determined to evaluate the sensitivity of the analysis corresponding to the concentrations of the analyte that resulted in signal-to-noise ratios of 3 (LOD) and 10 (LOQ) following the guidelines from ICH Q2(R1) on validation of analytical procedures.(53) The LOD and LOQ were calculated as LOD = 3.3σ/S and LOQ = 10σ/S, where σ corresponds to the standard deviation of the response and S corresponds to the slope of the calibration curve, which was estimated from the calibration curve of the analyte (Table S1, Supporting Information).

Cytotoxicity Assays

The cytotoxicity of compounds (1–5) obtained from P. madagascariensis extracts was evaluated in a battery of human cell lines (MDA-MB-231, MCF-7, and HCT116) using the sulfurhodamine B (SRB) assay according to a procedure supervised by Saraiva et al.(54,55) Briefly, cells were plated in 96-well plates (5.0 × 103 cells/well) and incubated for 24 h at 37 °C in a humidified atmosphere with 5% CO2. Then, cells were exposed to serial dilutions of each compound (1.85–150 μM) and incubated for another 48 h. Following fixation with 10% trichloroacetic acid, cells were stained with 0.4% (w/v) sulforhodamine B and then washed with 1% acetic acid to remove the unbound stain. The adsorbed dye was dissolved with 10 mM Tris buffer (pH 10.5), and the absorbance was measured at 510 nm in a microplate reader (Biotek Instruments Inc., Synergy MX, USA). Doxorubicin was used as positive control. In Table 3, Student’s t test was used to compare the GI50 values of compounds (3–5) to that of compound 2 in the MCF-7 cell line. All P values were based on the two-sided statistical analysis, and P < 0.05 was considered to be statistically significant.
The cytotoxic effects of the compounds toward NCI-H460, NCI-H460/R, and MCR-5 cell lines were further assessed by the MTT colorimetric assay based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) into a formazan dye by active mitochondria of living cells according to the procedure described by Pesic et al.(34,56) Briefly, cells were plated in 96-well plates, inoculated with the compounds (2.5–50 μM), and incubated for 72 h at 37 °C in a humidified atmosphere with 5% CO2. Then, 100 μL of MTT solution (1 mg/mL) was added to each well, and the plates were incubated at 37 °C for 4 h. The formazan product was dissolved by adding 200 μL of DMSO per well, and absorbance was measured at 540 nm in a microplate reader (LKB 5060–006 Micro Plate Reader, Vienna, Austria). Paclitaxel was used as positive control.
Cell viability (%) was calculated as a fraction of the absorbance shown by nontreated cells (control), and the GI50 values, corresponding to the concentration of the compound that inhibits 50% of cell growth, were determined. At least two independent experiments in triplicate were performed for each test compound. Statistical analysis was performed using GraphPad Prism 6.01 (GraphPad Software Inc., La Jolla, CA, USA). Results are presented as mean ± SD. Normality was checked by Column Statistics of GraphPad Prism 6 software—Shapiro–Wilk normality test. Accordingly, the unpaired t test from row data after the MTT measurement was applied.

Supporting Information

ARTICLE SECTIONS
Jump To

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00512.

  • 1H NMR and 13C NMR spectra of compound (3), HPLC-DAD analytical profile of plant extracts and UV-spectra overlay, and analytical parameters for HPLC-DAD quantification method (PDF)

The authors declare no competing financial interest.

Terms & Conditions

Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

Acknowledgments

ARTICLE SECTIONS
Jump To

The authors thank Ernst van Jaarsveld (Kirstenbosch National Botanic Gardens, South Africa) for providing cuttings of the Plectranthus plants, Teresa Vasconcelos (Instituto Superior Agrário, Lisbon, Portugal) for the growing of the plants, and Maria João Cebola and Paula Pereira for the preparation of the supercritical fluid extracts. D.M. is thankful for grant PADDIC 2013-2014 (ALIES-COFAC), part of the PhD program in Health Sciences from Universidad de Alcalá and Universidade Lusófona. The authors would also like to thank to Fundação para a Ciência e Tecnologia for financial support under the reference UID/DTP/04567/2016 and UID/MULTI/04378/2013.

References

ARTICLE SECTIONS
Jump To

This article references 56 other publications.

  1. 1
    Lukhoba, C. W.; Simmonds, M. S. J.; Paton, A. J. Plectranthus: a review of ethnobotanical uses. J. Ethnopharmacol. 2006, 103, 1– 24,  DOI: 10.1016/j.jep.2005.09.011
    [Crossref], [PubMed], [CAS], Google Scholar
    1
    Plectranthus: a review of ethnobotanical uses
    Lukhoba Catherine W; Simmonds Monique S J; Paton Alan J
    Journal of ethnopharmacology (2006), 103 (1), 1-24 ISSN:0378-8741.
    Plectranthus is a large and widespread genus with a diversity of ethnobotanical uses. The genus is plagued with numerous nomenclatural disharmonies that make it difficult to collate accurate data on the uses. The aim of this review is to gather together all ethnobotanical information on Plectranthus and to map the data onto the most up-to-date phylogenetic classification in order to see if there are similar uses among related species and hence provide a framework for the prediction and exploration of new uses of species. The uses of 62 species of Plectranthus were mapped onto a current phylogeny based on DNA sequence data. The phylogeny reveals two major Clades, 1 and 2. The members of Clade 1 (corresponding to the formally recognized genus Coleus) were richer in number and diversity of uses than members of Clade 2 (comprising the remaining species of Plectranthus). The high incidence of synonymy can lead to problems in uncovering a species' ethnobotanical profile. About 30% of all citations of Plectranthus use a synonym and most of the synonyms are attributed to 10 of the most used species, 9 of which are in Clade 1. Members of the 'Coleus' Clade are the most studied group both taxonomically and economically. The higher incidence of study may be as a result of the higher diversity of uses and the fact that species in Clade 1, such as Plectranthus barbatus, Plectranthus amboinicus and Plectranthus mollis, are geographically more widespread than those in Clade 2. Plectranthus species in Clade 1 are frequently used as medicines and are used to treat a range of ailments, particularly digestive, skin, infective and respiratory problems. Plectranthus used as foods, flavours, fodder and materials are also mostly found in Clade 1. Monoterpenoids, sesquiterpenoids, diterpenoids and phenolics have been reported in species of Plectranthus. The abietane diterpenoids are the most diverse of the diterpenoids isolated from species of Plectranthus. The labdane diterpenoid, forskolin, occurs in Plectranthus barbatus and could explain some of the traditional uses of this species. This review highlights the fact that not enough is known about the chemistry of other species of Plectranthus to explain their traditional uses.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnjtVajtg%253D%253D&md5=2cfd3b10a293029e1217a2ba4e4b025d
  2. 2
    Gaspar-Marques, C.; Rijo, P.; Simões, M. F.; Duarte, M. A.; Rodríguez, B. Abietanes from Plectranthus grandidentatus and P. hereroensis against methicillin- and vancomycin-resistant bacteria. Phytomedicine 2006, 13, 267– 271,  DOI: 10.1016/j.phymed.2005.06.002
    [Crossref], [PubMed], [CAS], Google Scholar
    2
    Abietanes from Plectranthus grandidentatus and P. hereroensis against methicillin- and vancomycin-resistant bacteria
    Gaspar-Marques, C.; Rijo, P.; Simoes, M. F.; Duarte, M. A.; Rodriguez, B.
    Phytomedicine (2006), 13 (4), 267-271CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
    The antimicrobial activity of 10 natural abietanes isolated from Plectranthus grandidentatus and P. hereroensis acetonic ext. was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). The results revealed that the most active diterpenes were coleon U (1), 7α-acetoxy-6β-hydroxyroyleanone (2) and horminone (3). Min. inhibitory concn. (MIC) values ranging 0.98-15.63 μg/mL were obtained for MRSA clin. strains, and MIC values of 15.63 and 31.25 μg/mL were obtained for VRE clin. strains. Some structure-activity relationships are emphasized.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFyltb0%253D&md5=a60ee336e13fac37ee516d20a7aab022
  3. 3
    Rijo, P.; Faustino, C.; Simões, M. F. Antimicrobial natural products from Plectranthus plants. In Microbial Pathogens and Strategies for Combating Them: Science, Technology and Education; Méndez-Vilas, A., Ed.; Formatex: Badajoz, 2013; pp 922– 931.
    Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Rijo, P.; Simões, M. F.; Francisco, A. P.; Rojas, R.; Gilman, R. H.; Vaisberg, A. J.; Rodríguez, B.; Moiteiro, C. Antimycobacterial metabolites from Plectranthus: royleanone derivatives against Mycobacterium tuberculosis strains. Chem. Biodiversity 2010, 7, 922– 932,  DOI: 10.1002/cbdv.200900099
    [Crossref], [PubMed], [CAS], Google Scholar
    4
    Antimycobacterial metabolites from Plectranthus: Royleanone derivatives against Mycobacterium tuberculosis strains
    Rijo, Patricia; Simoes, M. Fatima; Francisco, A. Paula; Rojas, Rosario; Gilman, Robert H.; Vaisberg, Abraham J.; Rodriguez, Benjamin; Moiteiro, Cristina
    Chemistry & Biodiversity (2010), 7 (4), 922-932CODEN: CBHIAM; ISSN:1612-1872. (Verlag Helvetica Chimica Acta)
    The antimycobacterial activities of eight diterpenes, 1-8, isolated previously from Plectranthus and eleven esters, 9-19, of 7α-acetoxy-6β,12-dihydroxyabieta-8,12-diene-11,14-dione (5) were evaluated against the MTB strains H37Rv and MDR. Only diterpenoids with a quinone framework revealed anti-MTB activity. Abietane 5 and its 6,12-dibenzoyl, 12-methoxybenzoyl, 12-chlorobenzoyl, and 12-nitrobenzoyl esters, 9, 11, 12, and 13, resp., showed potent activities against the MDR strain with MIC values between 3.12 and 0.39 μg/mL. Cytotoxic activities towards 3T3 and Vero cells were also evaluated. Compd. 11, with the best selectivity index, may be a suitable lead for further chem. modifications. The complete structural elucidation of the new esters, 9-14, 16, 18, and 19, as well as the NMR data of known derivs. 15 and 17 are reported.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltVygtr8%253D&md5=02479678bab8c5f76bab9c629a2bf3ce
  5. 5
    Kubínová, R.; Pořízková, R.; Navrátilová, A.; Farsa, O.; Hanáková, Z.; Bačinská, A.; Cížek, A.; Valentová, M. Antimicrobial and enzyme inhibitory activities of the constituents of Plectranthus madagascariensis (Pers.) Benth. J. Enzyme Inhib. Med. Chem. 2014, 6366, 1– 4,  DOI: 10.3109/14756366.2013.848204
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Falé, P. L.; Borges, C.; Madeira, P. J. A.; Ascensão, L.; Araújo, M. E. M.; Florêncio, M. H.; Serralheiro, M. L. M. Rosmarinic acid, scutellarein 4′-methyl ether 7-O-glucuronide and (16S)-coleon E are the main compounds responsible for the antiacetylcholinesterase and antioxidant activity in herbal tea of Plectranthus barbatus (“falso boldo”). Food Chem. 2009, 114, 798– 805,  DOI: 10.1016/j.foodchem.2008.10.015
    [Crossref], [CAS], Google Scholar
    6
    Rosmarinic acid, scutellarein 4'-methyl ether 7-O-glucuronide and (16S)-coleon E are the main compounds responsible for the antiacetylcholinesterase and antioxidant activity in herbal tea of Plectranthus barbatus ("falso boldo")
    Fale, Pedro L.; Borges, Carlos; Madeira, Paulo J. Amorim; Ascensao, Lia; Araujo, Maria Eduarda M.; Florencio, Maria Helena; Serralheiro, Maria Luisa M.
    Food Chemistry (2009), 114 (3), 798-805CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)
    Plectranthus barbatus, known as "falso boldo" in Brazil, is used in herbal tea or cooked as a vegetable. Infusions and decoctions of leaves from P. barbatus were analyzed for their inhibition of acetylcholinesterase and their antioxidant activity. The decoction showed high inhibition activity (31% inhibition with 0.5 mg of ext./mL) and also high antioxidant activity (IC50 = 45.8 ± 0.5 μg of dry ext./mL in the DPPH test; IC50 = 69.8 ± 3.1 μg of dry ext./mL in the β-carotene-linoleic acid test). Rosmarinic acid, scutellarein 4'-Me ether 7-O-glucuronide and (16S)-coleon E were the main constituents identified. These compds. have antiacetylcholinesterase activity. Rosmarinic acid and the scutellarein deriv. have IC50 = 440 μg/mL and 1 mg/mL, resp. One milligram per mL of (16S)-coleon E showed 61% inhibition of the enzyme. Other Plectranthus species, P. eckloni, P. fruticosus, P. lanuginosus and P. verticillatus, were also analyzed and the results obtained correlated with the content in rosmarinic acid.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvFansLo%253D&md5=33d02dfb3a42de03f164564fc172ba2a
  7. 7
    Gurgel, A. P. A. D.; da Silva, J. G.; Grangeiro, A. R. S.; Oliveira, D. C.; Lima, C. M. P.; da Silva, A. C. P.; Oliveira, R. A. G.; Souza, I. A. In vivo study of the anti-inflammatory and antitumor activities of leaves from Plectranthus amboinicus (Lour.) Spreng (Lamiaceae). J. Ethnopharmacol. 2009, 125, 361– 363,  DOI: 10.1016/j.jep.2009.07.006
    [Crossref], [PubMed], [CAS], Google Scholar
    7
    In vivo study of the anti-inflammatory and antitumor activities of leaves from Plectranthus amboinicus (Lour.) Spreng (Lamiaceae)
    Gurgel Ana Pavla A Diniz; da Silva Jackeline G; Grangeiro Ana Ruth S; Oliveira Danielli C; Lima Cynthia M P; da Silva Aldo C P; Oliveira Rinalda A G; Souza Ivone A
    Journal of ethnopharmacology (2009), 125 (2), 361-3 ISSN:.
    ETHNOPHARMACOLOGICAL RELEVANCE: Plectranthus amboinicus (Lour.) Spreng is a medicinal specie often used in Brazil, especially in Northeast Region, for the treatment of several diseases including inflammations and cancer. AIM OF THE STUDY: To evaluate the anti-inflammatory and antitumor activities of the hydroalcoholic extract from leaves of P. amboinicus in an attempt to determine whether the medicinal uses are supported by pharmacological effects. MATERIALS AND METHODS: Anti-inflammatory activity was determined by carrageenan-induced paw edema method. The antitumor effect was evaluated in an in vivo experimental study, using the following tumors: Sarcoma-180 and Erlich ascite carcinoma. RESULTS: There were statistically significant decreases (p<.05) of edema paw in at the doses of 150, 250 and 350 mg/kg (i.p.) of the hydroalcoholic extract of P. amboinicus. Similarly, the administration of P. amboinicus at the doses of 100, 150, 250 and 350 mg/kg (i.p.) inhibited the growth of sarcoma-180 and Ehrlich ascite carcinoma tumors in mice. CONCLUSION: The results suggest that the hydroalcoholic extract of P. amboinicus possesses anti-inflammatory and antitumor activities, supporting the folk use of this medicinal specie.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrntFWgsg%253D%253D&md5=c8663592dfe721dc0fe45123cbe83501
  8. 8
    Minker, C.; Sheridan, H.; O’Meara, J.; Johnse, L. V.; Hook, I.; Lobstein, A.; Frankish, N. In vivo and in vitro evaluation of anti-inflammatory activity and cytotoxicity of extracts of seven Plectranthus species. Planta Med. 2007, 73, 074  DOI: 10.1055/s-2007-986856
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Burmistrova, O.; Perdomo, J.; Simões, M. F.; Rijo, P.; Quintana, J.; Estévez, F. The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells. Phytomedicine 2015, 22, 1009– 1016,  DOI: 10.1016/j.phymed.2015.06.013
    [Crossref], [PubMed], [CAS], Google Scholar
    9
    The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells
    Burmistrova, Olga; Perdomo, Juan; Simoes, M. Fatima; Rijo, Patricia; Quintana, Jose; Estevez, Francisco
    Phytomedicine (2015), 22 (11), 1009-1016CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
    Abietane diterpenes have attracted much attention because they display a wide range of biol. activities, including antitumor activities. These compds. are the most diverse of the diterpenoids isolated from species of Plectranthus. Naturally occurring diterpene parvifloron D is the main phytochem. constituent of Plectranthus ecklonii. To examine the therapeutic potential of the plant, we evaluated whether parvifloron D displays cytotoxicity against human tumor cells.The cytotoxicity was analyzed by colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was evaluated by fluorescent microscopy, transmission electron microscopy, flow cytometric anal. of annexin V-FITC and propidium iodide-stained cells and DNA fragmentation. Protein expression and processing and release of mitochondrial proteins were analyzed by Western blot. Caspase activity was detd. using colorimetric substrates. The membrane potential and intracellular reactive oxygen species were detected by flow cytometry.Parvifloron D displays strong cytotoxic properties against leukemia cells (HL-60, U-937, MOLT-3 and K-562) and in particular P-glycoprotein-overexpressing K-562/ADR cells, but has only weak cytotoxic effects on peripheral blood mononuclear cells (PBMCs). Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to parvifloron D-induced cytotoxicity. Growth inhibition of HL-60 cells that was triggered by parvifloron D was found to be caused by a rapid induction of apoptotic cell death. This apoptosis was prevented by the non-specific caspase inhibitor z-VAD-fmk, and by the selective caspase-9 inhibitor z-LEHD-fmk. Cell death induced by parvifloron D was found to be (i) assocd. with the dissipation of the mitochondrial membrane potential and the release of cytochrome c, (ii) amplified by inhibition of extracellular signal-regulated kinases (ERKs) 1/2 signaling and (iii) caused by a mechanism dependent on intracellular reactive oxygen species generation.Parvifloron D is a potent cytotoxic compd. against several human tumor cells and also a fast and potent apoptotic inducer in leukemia cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtF2itbvF&md5=24ffbf1637360ebd73364467a31add30
  10. 10
    Cerqueira, F.; Cordeiro-da-Silva, A.; Gaspar-Marques, C.; Simões, F.; Pinto, M. M. M.; Nascimento, M. S. J. Effect of abietane diterpenes from Plectranthus grandidentatus on T- and B-lymphocyte proliferation. Bioorg. Med. Chem. 2004, 12, 217– 223,  DOI: 10.1016/j.bmc.2003.10.006
    [Crossref], [PubMed], [CAS], Google Scholar
    10
    Effect of abietane diterpenes from Plectranthus grandidentatus on T- and B-lymphocyte proliferation
    Cerqueira, F.; Cordeiro-Da-Silva, A.; Gaspar-Marques, C.; Simoes, F.; Pinto, M. M. M.; Nascimento, M. S. J.
    Bioorganic & Medicinal Chemistry (2004), 12 (1), 217-223CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
    Five known abietane diterpenes of the royleanone and coleon type, namely, fatty acid esters of 7α-acyloxy-6β-hydroxyroyleanone (1), grandidone A (2), 7α-acetoxy-6β-hydroxyroyleanone (3), 6β,7α-dihydroxyroyleanone (4) and coleon U (5), isolated from Plectranthus grandidentatus, were evaluated for their effect on the proliferation of human lymphocytes induced by the mitogen PHA. All except 4, showed a dose-dependent suppressor effect, with 3 yielding the most potent antiproliferative activity, followed by 5. These two compds., that represent diterpenes of the royleanone and coleon type resp., were also shown to be potent inhibitors of mouse splenocyte proliferation induced by ConA or LPS mitogens. However, the sensitivity of ConA-stimulated splenocytes to their suppressive effect was higher, suggesting a preferential inhibition of T-lymphocyte proliferation. The antiproliferative activity of 3 seemed to be exerted without affecting the expression of the lymphocyte activation marker CD69. On the contrary, 5 was shown to reduce the expression of CD69 of TCD8+ and B-cells, suggesting a relationship between its antiproliferative effect and the expression of this early marker of activation on these cell populations. The capacity of 5 to induce apoptosis on ConA-stimulated splenocytes could also be related with its antiproliferative activity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVSjtLfL&md5=3f3d1738aeb903d23463a145f4ffbd65
  11. 11
    Marques, C. G.; Pedro, M.; Simões, M. F. A.; Nascimento, M. S. J.; Pinto, M. M. M.; Rodríguez, B. Effect of abietane diterpenes from Plectranthus grandidentatus on the growth of human cancer cell lines. Planta Med. 2002, 68, 839– 840,  DOI: 10.1055/s-2002-34407
    [Crossref], [PubMed], [CAS], Google Scholar
    11
    Effect of abietane diterpenes from plectranthus grandidentatus on the growth of human cancer cell lines
    Marques, Cristina Caspar; Pedro, Madalena; Simoes, M. Fatima A.; Nascimento, Maria Sao Jose; Pinto, Madalena M. M.; Rodriguez, Benjamin
    Planta Medica (2002), 68 (9), 839-840CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
    Five known abietane diterpenes, fatty acid esters of 7α-acyloxy-6β-hydroxyroyleanone (1), grandidone A (2), 7α-acetoxy-6β-hydroxyroyleanone (3), 6β,7α-dihydroxyroyleanone (4), and coleon U (5), isolated from Plectranthus grandidentatus Gurke, were evaluated for their in vitro antiproliferative activity against five human cancer cell lines MCF-7, NCI-H460, SF-268, TK-10, and UACC-62. Coleon U (5) exhibited the strongest effect among all the assayed compds. The abietane 3 revealed also a strong inhibitory effect while diterpenes 2 and 4 inhibited only slightly the growth of all cancer cell lines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVGns7c%253D&md5=e397eaacc48a2997b669c5591b28ceb6
  12. 12
    Saeed, M. E. M.; Meyer, M.; Hussein, A.; Efferth, T. Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells. J. Ethnopharmacol. 2016, 186, 209– 223,  DOI: 10.1016/j.jep.2016.04.005
    [Crossref], [PubMed], [CAS], Google Scholar
    12
    Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells
    Saeed, Mohamed E. M.; Meyer, Marion; Hussein, Ahmed; Efferth, Thomas
    Journal of Ethnopharmacology (2016), 186 (), 209-223CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
    Traditional medicine plays a major role for primary health care worldwide. Cancer belongs to the leading disease burden in industrialized and developing countries. Successful cancer therapy is hampered by the development of resistance towards established anticancer drugs. In the present study, we investigated the cytotoxicity of 29 exts. from 26 medicinal plants of South-Africa against leukemia cell lines, most of which are used traditionally to treat cancer and related symptoms. We have investigated the plant exts. for their cytotoxic activity towards drug-sensitive parental CCRF-CEM leukemia cells and their multidrug-resistant P-glycoprotein-overexpressing subline, CEM/ADR5000 by means of the resazurin assay. A panel of 60 NCI tumor cell lines have been investigated for correlations between selected phytochems. from medicinal plants and the expression of resistance-conferring genes (ABC-transporters, oncogenes, tumor suppressor genes). Seven exts. inhibited both cell lines (Acokanthera oppositifolia, Hypoestes aristata, Laurus nobilis, Leonotis leonurus, Plectranthus barbatus, Plectranthus ciliates, Salvia apiana). CEM/ADR5000 cells exhibited a low degree of cross-resistance (3.35-fold) towards the L. leonurus ext., while no cross-resistance was obsd. to other plant exts., although CEM/ADR5000 cells were highly resistant to clin. established drugs. The log10IC50 values for two out of 14 selected phytochems. from these plants (acovenoside A and ouabain) of 60 tumor cell lines were correlated to the expression of ABC-transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS) and tumor suppressors (TP53). Sensitivity or resistance of the cell lines were not statistically assocd. with the expression of these genes, indicating that multidrug-resistant, refractory tumors expressing these genes may still respond to acovenoside A and ouabain. The bioactivity of South African medicinal plants may represent a basis for the development of strategies to treat multidrug-resistant tumors either by phytotherapeutic approaches with whole plant prepns. or by classical drug development with isolated compds. such as acovenoside A or ouabain.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsVeis7w%253D&md5=e4edb6e652bc5b788d34f71369a7116b
  13. 13
    Hasibuan, P. A. Z.; Rosidah; Ilyas, S.; Nasution, M. P. Antioxidant and cytotoxic activities of Plectranthus amboinicus (Lour.) Spreng. extracts. Int. J. Pharm. Teach. Pract. 2013, 4, 755– 758
    Google Scholar
    There is no corresponding record for this reference.
  14. 14
    Ramalakshmi, P.; Subramanian, N.; Saravanan, R.; Mohanakrishnan, H.; Muthu, M. Anticancer effect of Coleus amboinicus (Karpporavalli) on human lung cancer cell line (A549). Int. J. Dev. Res. 2014, 4, 2442– 2449
    Google Scholar
    There is no corresponding record for this reference.
  15. 15
    Arcanjo, D. D. R.; Albuquerque, A. C. M.; Melo-Neto, B.; Santana, L. C. L. R.; Medeiros, M. G. F.; Citó, A. M. G. L. Bioactivity evaluation against Artemia salina Leach of medicinal plants used in Brazilian Northeastern folk medicine. Braz. J. Biol. 2012, 72, 505– 509,  DOI: 10.1590/S1519-69842012000300013
    [Crossref], [PubMed], [CAS], Google Scholar
    15
    Bioactivity evaluation against Artemia salina Leach of medicinal plants used in Brazilian Northeastern folk medicine
    Arcanjo D D R; Albuquerque A C M; Melo-Neto B; Santana L C L R; Medeiros M G F; Cito Amgl
    Brazilian journal of biology = Revista brasleira de biologia (2012), 72 (3), 505-9 ISSN:.
    The brine shrimp (Artemia salina Leach) lethality bioassay offers an advantage in standardization and quality control of botanical products. This test is well correlated with antitumor activity (cytotoxicity) and can be used to monitor the activity of bioactive natural products. This paper reports the bioactivity of ethanol extracts from seven medicinal plants from the Northeast of Brazil (Acmella uliginosa, Ageratum conyzoides, Eugenia uniflora, Plectranthus neochilus, Moringa oleifera, Justicia pectoralis and Equisetum sp.) against Artemia salina. Biological activity was evaluated for extracts at 1, 10, 100, and 1000 μg/mL in triplicate, and the mean lethal concentration values (LC50) were obtained by probit analysis. The species Acmella uliginosa showed the highest bioactivity, and its flower extract was more active than its leaf extract.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bot1ansg%253D%253D&md5=56a6c8afeb0eb69af2b7e9291b3918c5
  16. 16
    Borges, G. A.; Ferreira, J. F.; Elias, S. T.; Guerra, E. N. S.; Silveira, D.; Simeoni, L. A. Cytotoxic effect of Plectranthus neochilus extracts in head and neck carcinoma cell lines. Afr. J. Pharm. Pharmacol. 2016, 10, 157– 163,  DOI: 10.5897/AJPP2015.4355
    [Crossref], [CAS], Google Scholar
    16
    Cytotoxic effect of Plectranthus neochilus extracts in head and neck carcinoma cell lines
    Borges, Gabriel Alvares; Ferreira, Juliana Freitas; Elias, Silvia Taveira; Guerra, Eliete Neves Silva; Silveira, Damaris; Simeoni, Luiz Alberto
    African Journal of Pharmacy and Pharmacology (2016), 10 (10), 157-163CODEN: AJPPHM; ISSN:1996-0816. (Academic Journals)
    Following a tendency of studying the potential effects of plant exts. to cancer, this study aimed to evaluate in vitro the cytotoxic activity of Plectranthus neochilus (PN) exts. and its fractions in head and neck squamous cell carcinoma (HNSCC) cell lines and assess their tumor specificity. MTT assay was conducted with two HNSCC cell lines, FaDu (hypopharynx carcinoma) and SCC-25 (tongue carcinoma), one keratinocyte (HaCat) and one fibroblast (L929) cell line. Two PN leaf crude exts., one ethanolic (E) and one hexanic (H), and their nine fractions were tested. A dose-response curve was performed with hexane PNH fraction and a tumor specificity index (TSI) was calcd. For all cell lines studied, almost all exts. and fractions resulted in cell viability lower than 50%. Hexane and methanol PNH fractions were exceptions, causing a significantly low viability in SCC-25 (17.16 and 34.53%, resp.), but higher than 50% in FaDu, HaCat and L929. The dose-response curve with hexane PNH fraction resulted in a CC50 of 540.9 μg/mL for FaDu, 550 μg/mL for L929, 762.1 μg/mL for HaCat and 274.2 μg/mL for SCC-25. The TSI L929/FaDu was 1.01, HaCat/FaDu was 1.40, L929/SCC-25 was 2.00 and HaCat/SCC-25 was 2.77. TSIs indicate its specificity for tongue carcinoma cells, when compared to fibroblasts and keratinocytes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVyiurnK&md5=f89d87953053dc8e3a015a04390df493
  17. 17
    Agarwal, K. C.; Parks, R. E., Jr. Forskolin: a potential antimetastatic agent. Int. J. Cancer 1983, 32, 801– 804,  DOI: 10.1002/ijc.2910320622
    [Crossref], [PubMed], [CAS], Google Scholar
    17
    Forskolin: a potential antimetastatic agent
    Agarwal, Kailash C.; Parks, Robert E., Jr.
    International Journal of Cancer (1983), 32 (6), 801-4CODEN: IJCNAW; ISSN:0020-7136.
    The effect of forskolin [66575-29-9] on tumor-induced human platelet aggregation and pulmonary tumor colonization in mice was examd. Forskolin (2 μM) strongly inhibited B-16 F10 melanoma cell-induced human platelet aggregation. A single dose of forskolin (82 μg/mouse) administered i.p. 30 or 60 min prior to tail vein injection of cultured B16-F10 cells reduced tumor colonization in the lungs by >70%. Thus, forskolin could prove of value for the prevention of metastasis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtFCltQ%253D%253D&md5=90dd9b48eb6e747afe5b6ee630b42389
  18. 18
    McEwan, D. G.; Brunton, V. G.; Baillie, G. S.; Leslie, N. R.; Houslay, M. D.; Frame, M. C. Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res. 2007, 67, 5248– 5257,  DOI: 10.1158/0008-5472.CAN-07-0097
    [Crossref], [PubMed], [CAS], Google Scholar
    18
    Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4-Regulated Compartment via Effects on Phosphoinositide 3-Kinase
    McEwan, David G.; Brunton, Valerie G.; Baillie, George S.; Leslie, Nicholas R.; Houslay, Miles D.; Frame, Margaret C.
    Cancer Research (2007), 67 (11), 5248-5257CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cAMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G1 by inducing p27Kip1 and primes cells for apoptosis on addn. of rolipram. The effect of the low-dose forskolin/rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a crit. intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homolog, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concns. in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clin. development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVaitr8%253D&md5=022bebe0d7d6bc137110d1b2d1039be4
  19. 19
    Burmistrova, O.; Simões, M. F.; Rijo, P.; Quintana, J.; Bermejo, J.; Estévez, F. Antiproliferative activity of abietane diterpenoids against human tumor cells. J. Nat. Prod. 2013, 76, 1413– 1423,  DOI: 10.1021/np400172k
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19
    Antiproliferative Activity of Abietane Diterpenoids against Human Tumor Cells
    Burmistrova, Olga; Simoes, M. Fatima; Rijo, Patricia; Quintana, Jose; Bermejo, Jaime; Estevez, Francisco
    Journal of Natural Products (2013), 76 (8), 1413-1423CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was detd. against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids contg. an abietane skeleton including taxodone and taxodione, as well as the semisynthetic derivs. 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone, 7α-acetoxy-6β-(4-nitro)benzoyloxyroyleanone, and 7α-acetoxy-6β-butyryloxyroyleanone, were the most cytotoxic compds. for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to abietane diterpene-induced cytotoxicity. Studies performed on HL-60 cells indicated that growth inhibition triggered by compds. taxodone, 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone, and 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone was caused by induction of apoptosis. This was prevented by the nonspecific caspase inhibitor Z-VAD-FMK and, in the case of compds. 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone and 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone, reduced by the selective caspase-8 inhibitor Z-IETD-FMK. Cell death induced by these abietane diterpenes was found to be assocd. with the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing factor), accompanied by dissipation of the mitochondrial membrane potential (ΔΨ), and modulated by inhibition of extracellular signal-regulated kinases signaling and the p38 mitogen-activated protein kinase pathway.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFeqsrbE&md5=6329ffd49138f45321e9241d44b00ce4
  20. 20
    Cowan, M. M. Plant products as antimicrobial agents. Clin. Microbiol. Rev. 1999, 12, 564– 582,  DOI: 10.1128/CMR.12.4.564
    [Crossref], [PubMed], [CAS], Google Scholar
    20
    Plant products as antimicrobial agents
    Cowan, Marjorie Murphy
    Clinical Microbiology Reviews (1999), 12 (4), 564-582CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
    A review with 253 refs. The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combining the Earth for phytochems. and "leads" which could be developed for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties. This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure and antimicrobial properties of phytochems. are also addressed. Since many of these compds. are currently available as unregulated botanical prepns. and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these prepns.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXntFSmsLc%253D&md5=278c87a12597ea390a55e963c04f6097
  21. 21
    Ladeiras, D.; Monteiro, C. M.; Pereira, F.; Reis, C. P.; Afonso, C. A. M.; Rijo, P. Reactivity of diterpenoid quinones: royleanones. Curr. Pharm. Des. 2016, 22, 1682– 1714,  DOI: 10.2174/1381612822666151211094521
    [Crossref], [PubMed], [CAS], Google Scholar
    21
    Reactivity of Diterpenoid Quinones: Royleanones.
    Ladeiras, Diogo; Monteiro, Carlos M.; Pereira, Filipe; Reis, Catarina P.; Afonso, Carlos A. M.; Rijo, Patricia
    Current Pharmaceutical Design (2016), 22 (12), 1682-1714CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    Naturally occurring abietane diterpenoids have been studied over the years and have shown to display a wide range of biol. activities. This review covers three main aspects of the abietane-type diterpenoids with hydroxy-p-quinone C ring, designated as royleanones. An overview of 1) the naturally occurrence, 2) chem. features and 3) the biol. activities of this abietane group of compds., including rearranged derivs., is here explained. Likewise, hemisynthetic and total synthetic procedures to obtain royleanones will be reviewed. Thus, the chem. of these bioactive compds. will be emphasized as well as their potential impact in the discovery of new macromol. targets and novel therapeutic drugs. This review contains about 190 refs. covering the years from 1962 to 2014 on royleanone studies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtVOlu74%253D&md5=d5a049e6f668211959cb7379e2e415ea
  22. 22
    Yulianto, W.; Andarwulan, N.; Giriwono, P. E.; Pamungkas, J. HPLC-based metabolomics to identify cytotoxic compounds from Plectranthus amboinicus (Lour.) Spreng against human breast cancer MCF-7cells. J. Chromatogr. B 2016, 1039, 28– 34,  DOI: 10.1016/j.jchromb.2016.10.024
    [Crossref], [PubMed], [CAS], Google Scholar
    22
    HPLC-based metabolomics to identify cytotoxic compounds from Plectranthus amboinicus (Lour.) Spreng against human breast cancer MCF-7Cells
    Yulianto, Wahid; Andarwulan, Nuri; Giriwono, Puspo Edi; Pamungkas, Joko
    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2016), 1039 (), 28-34CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
    The objective of this study was to identify the active compds. in Plectranthus amboinicus (Lour.) Spreng which play a role to inhibit viability of breast cancer MCF-7 cells using HPLC-based metabolomics approach. Five fractions of the plant ext. were obsd. including ethanol, hexane, chloroform, Et acetate and water fraction. There were 45 HPLC chromatograms resulted from 5 fractions with 3 replications and 3 wavelengths detection. The chromatograms were compared to the data of IC50 from MTT assay of each fraction against human breast cancer MCF-7 cells using metabolomics. The OPLS anal. result promptly pointed towards a chloroform fraction at retention time of 40.16-41.28 min that has the greatest contribution to the cytotoxic activity. The data of mass spectra indicated that an abietane diterpene namely 7-acetoxy-6-hydroxyroyleanone was the main compd. that contributed to the cytotoxic activity. This metabolomics application method can be used as a quick preliminary guideline to uncover the most dominant compd. related to the bioactivity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslyjtL%252FF&md5=51aeb2e1bb1fd3264574c7185d964451
  23. 23
    Wellsow, J.; Grayer, R. J.; Veitch, N. C.; Kokubun, T.; Lelli, R.; Kite, G. C.; Simmonds, M. S. J. Insect-antifeedant and antibacterial activity of diterpenoids from species of Plectranthus. Phytochemistry 2006, 67, 1818– 1825,  DOI: 10.1016/j.phytochem.2006.02.018
    [Crossref], [PubMed], [CAS], Google Scholar
    23
    Insect-antifeedant and antibacterial activity of diterpenoids from species of Plectranthus
    Wellsow, Julia; Grayer, Renee J.; Veitch, Nigel C.; Kokubun, Tetsuo; Lelli, Roberto; Kite, Geoffrey C.; Simmonds, Monique S. J.
    Phytochemistry (Elsevier) (2006), 67 (16), 1818-1825CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
    Bio-assay guided fractionation of an acetone ext. of leaf material from Plectranthus saccatus Benth. resulted in the isolation of a beyerane diterpenoid. This compd., characterized by spectroscopic methods as ent-3β-(3-methyl-2-butenoyl)oxy-15-beyeren-19-oic acid, showed insect antifeedant activity against Spodoptera littoralis. Known quinonoid abietane diterpenoids obtained from new sources included a mixt. of the (4R,19R) and (4R,19S) diastereoisomers of coleon A from P. aff. puberulentus J. K. Morton, coleon A lactone from P. puberulentus J. K. Morton, and coleon U and coleon U quinone from P. forsteri Marginatus' Benth. These compds., and the crude acetone exts. from the leaf surfaces of 11 species of Plectranthus, were tested for antifeedant activity against S. littoralis, antibacterial activity against Bacillus subtilis and Pseudomonas syringae and antifungal activity against Cladosporium herbarum. The coleon A mixt. showed potent antifeedant activity against S. littoralis, whereas coleon U showed the greatest antimicrobial activity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XovVSiur0%253D&md5=517b076023480a04d7b925926cab8d2e
  24. 24
    Matias, D.; Pereira, F.; Nicolai, M.; Roberto, A.; Saraiva, N.; Fernandes, A. S.; Simões, M. F.; Lanza, A. D.; Reis, C. P.; Rijo, P. Abietane diterpenes from Plectranthus madagascariensis: a cytotoxicity screening. Planta Med. 2014, 80, P1L152,  DOI: 10.1055/s-0034-1394809
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Miyase, T.; Rüedi, P.; Eugster, C. H. Diterpenoide Drüsenfarbstoffe aus Labiaten: Coleone U, V, W und 14-O-Formyl-coleon-V sowie 2 Royleanone aus Plectranthus myrianthus BRIQ.;cis- undtrans-A/B-6, 7-Dioxoroyleanon. Helv. Chim. Acta 1977, 60, 2770– 2779,  DOI: 10.1002/hlca.19770600830
    [Crossref], [CAS], Google Scholar
    25
    Diterpenoid leaf-gland pigments from Labiatae: coleons U, V, W, 14-O-formylcoleon V, and two royleanones from Plectranthus myrianthus Briq.; cis- and trans-A/B-6,7-dioxoroyleanone
    Miyase, Toshio; Ruedi, Peter; Eugster, Conrad Hans
    Helvetica Chimica Acta (1977), 60 (8), 2770-9CODEN: HCACAV; ISSN:0018-019X.
    From leaf-glands of the South-African P. myrianthus (Labiatae) the following diterpenoids were isolated and their structures established: coleon U, C20H26O5, I; coleon V, C20H26O5, II; coleon W, C22H28O8, III; 14-O-formyl-coleon V, C21H26O6, IV; 7α-formyloxy-6β-hydroxyroyleanone, C21H28O6; the already known 6β,7α-dihydroxyroyleanone and a dimeric abietane deriv. whose structure was not yet elucidated. This is the first record of a co-occurrence of coleons and royleanones in the same plant. In the course of chem. investigations of II and IV, the highly oxidized trans- and cis-A/B-6,7-dioxoroyleanones were obtained.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXhtVWmt78%253D&md5=9b9d283769dd663da8cd8333b75e58d0
  26. 26
    Mei, S.-X.; Jiang, B.; Niu, X.-M.; Li, M.-L.; Yang, H.; Na, Z.; Lin, Z.-W.; Li, C.-M.; Sun, H.-D. Abietane diterpenoids from Coleus xanthanthus. J. Nat. Prod. 2002, 65, 633– 637,  DOI: 10.1021/np0102049
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    26
    Abietane Diterpenoids from Coleus xanthanthus
    Mei, Shuang-Xi; Jiang, Bei; Niu, Xue-Mei; Li, Ma-Lin; Yang, Hui; Na, Zhi; Lin, Zhong-Wen; Li, Chao-Ming; Sun, Han-Dong
    Journal of Natural Products (2002), 65 (5), 633-637CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
    Eight new abietane diterpenoids, coleon U 11-acetate (1), 16-acetoxycoleon U 11-acetate (2), and xanthanthusins F-K (3-8), together with five known analogs, coleon U (9), 16-O-acetylcoleon C (10), coleon U-quinone (11), 8α,9α-epoxycoleon U-quinone (12), and xanthanthusin E (13), were isolated from the aerial parts of Coleus xanthanthus. The structures of 1-8 were elucidated on the basis of spectral methods. Compds. 1, 5, and 11-13 were evaluated for their cytotoxicity against K562 human leukemia cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XisVeksLc%253D&md5=3813ae7255496e2bb6ef8771bef22bdd
  27. 27
    Coutinho, I.; Pereira, G.; Simões, M. F.; Côrte-Real, M.; Gonçalves, J.; Saraiva, L. Selective activation of protein kinase C-δ and -ε by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U). Biochem. Pharmacol. 2009, 78, 449– 459,  DOI: 10.1016/j.bcp.2009.04.026
    [Crossref], [PubMed], [CAS], Google Scholar
    27
    Selective activation of protein kinase C-δ and -ε by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U)
    Coutinho, I.; Pereira, G.; Simoes, M. F.; Corte-Real, M.; Goncalves, J.; Saraiva, L.
    Biochemical Pharmacology (2009), 78 (5), 449-459CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
    6,11,12,14-Tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U) is a diterpene compd. isolated from Plectranthus grandidentatus with an antiproliferative effect on several human cancer cell lines. Herein, we studied the modulatory activity of coleon U on individual isoforms of the three protein kinase C (PKC) subfamilies, classical (cPKC-α and -βI), novel (nPKC-δ and -ε) and atypical (aPKC-ζ), using a yeast PKC assay. The results showed that, whereas the PKC activator phorbol-12-myristate-13-acetate (PMA) activated every PKC tested except aPKC, coleon U had no effect on aPKC and cPKCs. Besides, the effect of coleon U on nPKCs was higher than that of PMA. This revealed that coleon U was a potent and selective activator of nPKCs. The isoform-selectivity of coleon U for nPKC-δ and -ε was confirmed using an in vitro PKC assay. Most importantly, while PMA activated nPKCs inducing an isoform translocation from the cytosol to the plasma membrane and a G2/M cell cycle arrest, coleon U induced nPKCs translocation to the nucleus and a metacaspase- and mitochondrial-dependent apoptosis. This work therefore reconstitutes in yeast distinct subcellular translocations of a PKC isoform and the subsequent distinct cellular responses reported for mammalian cells. Together, our study identifies a new isoform-selective PKC activator with promising pharmacol. applications. Indeed, since coleon U has no effect on cPKCs and aPKC, recognized as anti-apoptotic proteins, and selectively induces an apoptotic pathway dependent on nPKC-δ and -ε activation, it represents a promising compd. for evaluation as an anti-cancer drug.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotFOlt70%253D&md5=2103d2bba7b9c1b304d4d6d57af90853
  28. 28
    Matias, D.; Bessa, C.; Simões, M. F.; Reis, C. P.; Saraiva, L.; Rijo, P. Natural products as lead protein kinase C modulators for cancer therapy. In Studies in Natural Products Chemistry: Bioactive Natural Products; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2016; pp 45– 79.
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Hensch, M.; Rüedi, P.; Eugster, C. H. Horminon, Taxochinon und weitere Royleanone aus 2 abessinischenPlectranthus-Spezies (Labiatae). Helv. Chim. Acta 1975, 58, 1921– 1934,  DOI: 10.1002/hlca.19750580707
    [Crossref], [CAS], Google Scholar
    29
    Horminone, taxoquinone, and other royleanones obtained from two Abyssinian Plectranthus species (Labiatae)
    Hensch, Marcel; Ruedi, Peter; Eugster, Conrad H.
    Helvetica Chimica Acta (1975), 58 (7), 1921-34CODEN: HCACAV; ISSN:0018-019X.
    Royleanone (I, R=H, Z=H2), 6,7-dehydroroyleanone (II), horminone (I, R=H, Z= α-OH, β-H), taxoquinone (I, R = H, Z=α-H,β-OH), 6β,7α-dihydroxyroyleanone (I, R=OH, Z=α-OAc,β-H), and 7-oxoroyleanone (I, R=H, Z=O) were isolated from the leaves of 2 Plectranthus species and their structures detd. on the basis of their uv and NMR spectra and by chem. correlation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XksVCitw%253D%253D&md5=163fdf1206635c0aa890280218f63bdd
  30. 30
    Brits, G. J.; Selchau, J.; van Deuren, G. Indigenous Plectranthus (Lamiaceae) from South Africa as new flowering pot plants. In XX International Eucarpia Symposium, Section Ornamentals, Strategies for New Ornamentals-Part I; 2001, 165– 170.
    Google Scholar
    There is no corresponding record for this reference.
  31. 31
    Van Zyl, R. L.; Khan, F.; Edwards, T. J.; Drewes, S. E. Antiplasmodial activities of some abietane diterpenes from the leaves of five Plectranthus species. S. Afr. J. Sci. 2008, 104, 62– 64
    [CAS], Google Scholar
    31
    Antiplasmodial activities of some abietane diterpenes from the leaves of five Plectranthus species
    van Zyl, R. L.; Khan, F.; Edwards, T. J.; Drewes, S. E.
    South African Journal of Science (2008), 104 (1/2), 62-64CODEN: SAJSAR; ISSN:0038-2353. (Academy of Science of South Africa)
    Seven known abietane diterpenes were isolated from five Plectranthus species, namely P. hadiensis, P. lucidus, P. eckloni, P. purpuratus subsp. purpuratus and P. purpuratus subsp. tongaensis. The seven compds. were tested for their antiplasmodial activity and for their ability to inhibit β-haematin formation. Overall, they showed good activity (IC50 values ranging from 3.11 to 14.65 μM), with one compd. being 62% as effective as chloroquine in inhibiting β-haematin formation. However, the cytotoxicity profile indicated a low degree of specificity towards the malaria parasite. When combined with quinine, three compds. interacted in an additive manner whereas one interacted synergistically.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFCgsLg%253D&md5=da766abebd9fb66935f6e8b541543f61
  32. 32
    Abdel-Mogib, M.; Albar, H. A.; Batterjee, S. M. Chemistry of the genus Plectranthus. Molecules 2002, 7, 271– 301,  DOI: 10.3390/70200271
    [Crossref], [CAS], Google Scholar
    32
    Chemistry of the genus Plectranthus
    Abdel-Mogib, M.; Albar, H. A.; Batterjee, S. M.
    Molecules [online computer file] (2002), 7 (2), 271-301CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)
    A review. This review presents the phytochem. constituents of the genus Plectranthus reported up to 1999. Only a tetrameric deriv. of caffeic acid was isolated from P. japonicus, but a group of long-chain alkylphenols, of possible taxonomic significance in the genus, was also isolated. As a genus of the subfamily Nepetoideae, Plectranthus is free from iridoid glycosides and rich in essential oil (i.e. > 0.5% volatile oil on a dry wt. basis). Diterpenoids are the more common secondary metabolites in Plectranthus. The majority of them are highly modified abietanoids. This seems to be similar to the pattern of diterpenoids obsd. for Salvia, but no clerodane diterpenoids were found in Plectranthus.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjs1Krurs%253D&md5=f734b6aaf81ac2dd57f5b7a6ce1d60b9
  33. 33
    Rijo, P.; Matias, D.; Fernandes, A. S.; Simões, M. F.; Nicolai, M.; Reis, C. P. Antimicrobial plant extracts encapsulated into polymeric beads for potential application on the skin. Polymer 2014, 6, 479– 490,  DOI: 10.3390/polym6020479
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  34. 34
    Pesic, M.; Markovic, J. Z.; Jankovic, D.; Kanazir, S.; Markovic, I. D.; Rakic, L.; Ruzdijic, S. Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell Line In Vitro by anticancer drugs. J. Chemother. 2006, 18, 66– 73,  DOI: 10.1179/joc.2006.18.1.66
    [Crossref], [PubMed], [CAS], Google Scholar
    34
    Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in vitro by anticancer drugs
    Pesic, M.; Markovic, J. Z.; Jankovic, D.; Kanazir, S.; Markovic, I. D.; Rakic, L.; Ruzdijic, S.
    Journal of Chemotherapy (Firenze, Italy) (2006), 18 (1), 66-73CODEN: JCHEEU; ISSN:1120-009X. (E.S.I.F.T. srl)
    Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concns. of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was obsd. Flow cytometry anal. showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the obsd. 15-fold increase in its mRNA concn. in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjtlGmsr4%253D&md5=14ba23316984daabf3638b5d064836e2
  35. 35
    Cleator, S.; Heller, W.; Coombes, R. C. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007, 8, 235– 244,  DOI: 10.1016/S1470-2045(07)70074-8
    [Crossref], [PubMed], [CAS], Google Scholar
    35
    Triple-negative breast cancer: therapeutic options
    Cleator Susan; Heller Wolfgang; Coombes R Charles
    The Lancet. Oncology (2007), 8 (3), 235-44 ISSN:1470-2045.
    Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7ivFKjsA%253D%253D&md5=d51518f923eb499081a8aca8f651357e
  36. 36
    Morse-Gaudio, M.; Connolly, J. M.; Rose, D. P. Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. Int. J. Oncol. 1998, 12, 1349– 1403,  DOI: 10.3892/ijo.12.6.1349
    [Crossref], [PubMed], [CAS], Google Scholar
    36
    Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype
    Morse-Gaudio, Michele; Connolly, Jeanne M.; Rose, David P.
    International Journal of Oncology (1998), 12 (6), 1349-1354CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
    Total protein kinase C (PKC) activity and the expression of 9 isoforms were detd. in the estrogen receptor (ER) pos. MCF-7 human breast cancer cell line, this line transfected to overexpress either PKC-α or erbB2, and in 3 ER neg. breast cancer cell lines. Relationships were sought between PKC and the expression of E-cadherin, α-catenin, and vimentin, and urokinase-type plasminogen activator (uPA). In general, PKC enzymic activity and the conventional isoforms PKC-α and -γ were higher in the ER neg., compared with the ER pos., cell lines. Over-expression of PKC-α by MCF-7 cells, with ER loss, was assocd. with the emergence of PKC-β expression and a relatively high level of PKC-γ, features typical of cells with increased proliferation rates; there was also a loss of PKC-ζ, consistent with acquisition of the metastatic phenotype. Transfection to overexpress erbB2, with ER retention and slowed growth, produced a decrease in PKC-α and -γ. Vimentin was expressed by the ER neg. MDA-MB-231, MDA-MB-435 and PKC-α-transfected MCF-7 cells; they also showed loss of E-cadherin and, apart from MDA-MB-435 cells, high levels of uPA secretion. The ER neg. SKBr-3 cell line was exceptional in that it had relatively low total PKC activity, low PKC-α and -γ expression and no emergence of vimentin despite loss of E-cadherin expression. Compared with the other two ER neg. cell lines, both the SKBr-3 and MDA-MB-435 cells had low PKC activity and uPA secretion. These results are consistent with the involvement of PKC, and notably the conventional isoforms, in the development of the metastatic phenotype, and specifically with the loss of E-cadherin and acquisition of vimentin expression, and the enhanced prodn. of uPA.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjs1KqtL0%253D&md5=f53205b5f96a9f0fe7440ee1726cb045
  37. 37
    Li, Z.; Wang, N.; Fang, J.; Huang, J.; Tian, F.; Li, C.; Xie, F. Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells. Oncol. Rep. 2012, 27, 1879– 1886,  DOI: 10.3892/or.2012.1728
    [Crossref], [PubMed], [CAS], Google Scholar
    37
    Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells
    Li, Zhihua; Wang, Na; Fang, Jieyu; Huang, Jintao; Tian, Fen; Li, Chaohong; Xie, Fukang
    Oncology Reports (2012), 27 (6), 1879-1886CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)
    This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-pos. human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-neg.) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric anal. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot anal. revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-pos. MCF-7 cells; while ER-neg. MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we obsd. that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFekt78%253D&md5=703cb6de8aa511f99b518e826b75d4ac
  38. 38
    Lønne, G. K.; Masoumi, K. C.; Lennartsson, J.; Larsson, C. Protein kinase Cδ supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway. J. Biol. Chem. 2009, 284, 33456– 33465,  DOI: 10.1074/jbc.M109.036186
    [Crossref], [PubMed], [CAS], Google Scholar
    38
    Protein kinase Cδ supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway
    Lonne, Gry Kalstad; Masoumi, Katarzyna Chmielarska; Lennartsson, Johan; Larsson, Christer
    Journal of Biological Chemistry (2009), 284 (48), 33456-33465CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase Cδ (PKCδ) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKCδ per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKCδ-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKCδ depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKCδ down-regulation. However, PKCδ silencing also induced increased MEK1/2 phosphorylation, indicating that PKCδ regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKCδ silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKCδ as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVCjtbzN&md5=de66a88bf9c52d033374312465f8590e
  39. 39
    Yokoyama, G.; Fujii, T.; Tayama, K.; Yamana, H.; Kuwano, M.; Shirouzu, K. PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells. Biochem. Biophys. Res. Commun. 2005, 327, 720– 726,  DOI: 10.1016/j.bbrc.2004.12.070
    [Crossref], [PubMed], [CAS], Google Scholar
    39
    PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells
    Yokoyama, Goro; Fujii, Teruhiko; Tayama, Kosuke; Yamana, Hideaki; Kuwano, Michihiko; Shirouzu, Kazuo
    Biochemical and Biophysical Research Communications (2005), 327 (3), 720-726CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)
    The effects of activating endogenous protein kinase C (PKC) on cell proliferation and the cell cycle were investigated by treating the breast cancer cell line SKBR-3 with phorbol 12-myristate 13 acetate (PMA). This inhibited cell growth in a concn.-dependent manner, causing a marked arrest of cells in G1. Pre-treatment with GF109203X completely blocked the antiproliferative effect of PMA, and pre-treatment with the PKCδ inhibitor rottlerin partially blocked it. Infecting SKBR-3 cells with an adenovirus vector contg. wild-type PKCδ, WTPKCδAdV, had similar effects on PMA. Infecting the cells with a dominant-neg. PKCδAdV construct blocked the growth inhibition induced by PMA. Downstream of PKC, PMA treatment inhibited extracellular signal-regulated kinase mitogen-activated protein kinase phosphorylation, up-regulated c-jun NH2-terminal kinase phosphorylation, and inhibited retinoblastoma (Rb) phosphorylation. These results strongly implicated PKC (mainly PKCδ) in the G1 arrest induced by PMA and suggested PKC as a target for breast cancer treatment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksFCqsQ%253D%253D&md5=d97402837c29f598bc86367b54810469
  40. 40
    Chaudhary, P. M.; Roninson, I. B. Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists. Oncol. Res. 1992, 4, 281– 290
    [PubMed], [CAS], Google Scholar
    40
    Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists
    Chaudhary, Preet M.; Roninson, Igor B.
    Oncology Research (1992), 4 (7), 281-90CODEN: ONREE8; ISSN:0965-0407.
    P-glycoprotein, encoded by the MDRI (multidrug resistance) gene, is a transmembrane efflux pump for various lipophilic compds. MDRI Is expressed in several types of normal human tissues and in a variety of tumors, where its expression has been correlated with resistance to chemotherapy. Some P-glycoprotein-overexpressing multidrug-resistant cell lines contain elevated amts. of protein kinase C (PKC). PKC activation was shown to increase the level of drug resistance in several cell lines, but the functional assocn. of PKC with P-glycoprotein-mediated multidrug resistance remains unclear. We have studied the effects of lymphocyte-activating agents on P-glycoprotein activity in normal human lymphocytes, and found that 12-O-tetradecanoylphorbol-13-acetate (TPA), an efficient agonist of PKC, increased the activity as well as the levels of P-glycoprotein in these cells. TPA also increased P-glycoprotein expression in several cell lines derived from different types of leukemias and solid tumors. The increase in MDRI gene expression was obsd. at both the protein and RNA levels. Induction of MDRI mRNA was apparent as early as two hours after the addn. of TPA. Diacylglycerol (DAG), a physiol. stimulant of PKC, also increased the expression of MDRI mRNA and P-glycoprotein. The induction of MDRI expression ty TPA and DAG was suppressed by staurosporine, a protein kinase inhibitor. The results suggest that MDRI gene expression in different cell types is regulated by a PKC-mediated pathway. This finding has implications for the emergence of multidrug resistance in vitro and in vivo.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhtFKgtrs%253D&md5=8dee316933f826f6cc70325b4daa9bec
  41. 41
    Al-Katib, A. M.; Smith, M. R.; Kamanda, W. S.; Pettit, G. R.; Hamdan, M.; Mohamed, A. N.; Chelladurai, B.; Mohammad, R. M. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res. 1998, 4, 1305– 1314
    [PubMed], [CAS], Google Scholar
    41
    Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts
    Al-Katib, Ayad M.; Smith, Mitchell R.; Kamanda, William S.; Pettit, George R.; Hamdan, Mohammed; Mohamed, Anwar N.; Chelladurai, Bhadrani; Mohammad, Ramzi M.
    Clinical Cancer Research (1998), 4 (5), 1305-1314CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor activity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (DLCL). The cell line (WSU-DLCL2) grows in liq. culture and forms s.c. tumors in mice with severe combined immune deficiency. WSU-DLCL2 is a mature B-cell line (IgGλ) that is neg. for EBV nuclear antigen, expresses the multidrug resistance phenotype, and has t(14;18)(q32;q21) plus other chromosomal aberrations. Exposure of the WSU-DLCL2 cells to Bryo1 in culture reversed the multidrug resistance phenotype within 24 h. A functional assay revealed a 4-fold increase in [3H]vincristine accumulation in Bryo1-treated cells compared with control. Vincristine (VCR), doxorubicin, Bryo1, and 1-β-D-arabinofuranosylcytosine showed no clin. significant activity when given alone to WSU-DLCL2-bearing severe combined immune deficiency mice. However, when given 24 h before each cytotoxic agent, Bryo1 substantially increased the antitumor activity of VCR but not 1-β-D-arabinofuranosylcytosine. There was a statistically significant (P < 0.001) decrease in the expression of P-glycoprotein in WSU-DLCL2 tumors taken from Bryo1-treated animals compared with untreated controls. In vivo, a competitive reverse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate that Bryo1-induced down-regulation of mdr1 might be one mechanism by which Bryo1 potentiates VCR activity. The sequential use of both agents resulted in clin. significant antitumor activity in this lymphoma model.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1yiu7k%253D&md5=de249ff25075e98bcfaa894bffe1aa17
  42. 42
    Fronza, M.; Murillo, R.; Ślusarczyk, S.; Adams, M.; Hamburger, M.; Heinzmann, B.; Laufer, S.; Merfort, I. In vitro cytotoxic activity of abietane diterpenes from Peltodon longipes as well as Salvia miltiorrhiza and Salvia sahendica. Bioorg. Med. Chem. 2011, 19, 4876– 4881,  DOI: 10.1016/j.bmc.2011.06.067
    [Crossref], [PubMed], [CAS], Google Scholar
    42
    In vitro cytotoxic activity of abietane diterpenes from Peltodon longipes as well as Salvia miltiorrhiza and Salvia sahendica
    Fronza, M.; Murillo, R.; Slusarczyk, S.; Adams, M.; Hamburger, M.; Heinzmann, B.; Laufer, S.; Merfort, I.
    Bioorganic & Medicinal Chemistry (2011), 19 (16), 4876-4881CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Phytochem. investigations of the n-hexane ext. from the roots of Peltodon longipes (Lamiaceae) resulted in the isolation of 12 known abietane diterpenes (1-12). Structures were established on the basis of one and two dimensional NMR spectroscopic data (1H and 13C, COSY, HSQC and HMBC), electron ionization mass spectrometric anal. (EIMS) as well as comparison with data from literature. These compds., as well as eight known diterpenes (13-19) from Salvia miltiorrhiza, and two from Salvia sahendica (20 and 21) were evaluated for their cytotoxic effects in human pancreatic (MIAPaCa-2) and melanoma (MV-3) tumor cell lines using the MTT assay. Tanshinone IIa (13), 7α-acetoxyroyleanone (1), 1,2-dihydrotanshinone (16) and cryptotanshinone (14) had the highest cytotoxic effects in MIAPaCa-2, displaying IC50 of 1.9, 4.7, 5.6, and 5.8 μM, resp. Structure-activity relationships of abietane diterpenoid quinones are discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFWhsr8%253D&md5=201441bde663628ed5abbce773b762a2
  43. 43
    Fronza, M.; Lamy, E.; Günther, S.; Heinzmann, B.; Laufer, S.; Merfort, I. Abietane diterpenes induce cytotoxic effects in human pancreatic cancer cell line MIA PaCa-2 through different modes of action. Phytochemistry 2012, 78, 107– 119,  DOI: 10.1016/j.phytochem.2012.02.015
    [Crossref], [PubMed], [CAS], Google Scholar
    43
    Abietane diterpenes induce cytotoxic effects in human pancreatic cancer cell line MIA PaCa-2 through different modes of action
    Fronza, Marcio; Lamy, Evelyn; Guenther, Stefan; Heinzmann, Berta; Laufer, Stefan; Merfort, Irmgard
    Phytochemistry (Elsevier) (2012), 78 (), 107-119CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
    Abietane diterpenes, esp. those contg. quinone moieties, are often reported to have cytotoxic effects on cancer cell lines. They deserve greater attention because several cancer chemotherapeutic agents also possess the quinone structural feature. To date, very little is known about their cytotoxic mol. modes of action. In the present study, 5 diterpenes, 7α-acetoxyroyleanone, horminone, royleanone, 7-ketoroyleanone, and sugiol which were previously isolated from the medicinal plant Peltodon longipes were shown to possess cytotoxic activity against the human pancreatic cancer cell line MIA PaCa-2. 7α-Acetoxyroyleanone, horminone, and royleanone were demonstrated to possess alkylating properties using the nucleophile 4-(4-nitrobenzyl)pyridine. However, no clear correlation between the alkylating properties and cytotoxicity of these diterpenes was obsd. Furthermore, the relaxation activity of human DNA topoisomerases I and II was found to be influenced by these compds., with 7-ketoroyleanone and sugiol being the most active. These 2 diterpenes preferentially inhibited topoisomerase I and exhibited lower IC50 values than the classical topoisomerase I inhibitor camptothecin. Mol. docking studies revealed possible interactions of diterpenes with topoisomerase I, indicating that these compds. do not form the drug-enzyme-DNA covalent ternary complex as obsd. with camptothecin. A binding pocket located at the surface of the DNA-interaction site was proposed. Moreover, the ability of the 5 diterpenes to generate DNA-strand breaks in single cells was confirmed using the alk. comet assay. As expected, these diterpenes also influenced cell cycle progression and arrested cells in different phases of the cell cycle, primarily the G1/G0 and S-phases. Interestingly, the diterpenes only exhibited a slight ability to induce apoptotic cell death and failed to generate intracellular reactive oxygen species. These results provide addnl. understanding of the cytotoxic effects of abietane diterpenes. Depending on their functional groups, we propose that abietane diterpenes utilize different mechanisms to induce cell death.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms12ntrY%253D&md5=a59ba3fd154c9ae8d8f565a2b4db1106
  44. 44
    Islam, M. T. Diterpenes and their derivatives as potential anticancer agents. Phytother. Res. 2017, 31, 691– 712,  DOI: 10.1002/ptr.5800
    [Crossref], [PubMed], [CAS], Google Scholar
    44
    Diterpenes and Their Derivatives as Potential Anticancer Agents
    Islam, Muhammad Torequl
    Phytotherapy Research (2017), 31 (5), 691-712CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
    As therapeutic tools, diterpenes and their derivs. have gained much attention of the medicinal scientists nowadays. It is due to their pledging and important biol. activities. This review congregates the anticancer diterpenes. For this, a search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chem. Society and misc. databases from Jan. 2012 to Jan. 2017 for the published articles. A total 28, 789 published articles were seen. Among them, 240 were included in this study. More than 250 important anticancer diterpenes and their derivs. were seen in the databases, acting in the different pathways. Some of them are already under clin. trials, while others are in the nonclin. and/or pre-clin. trials. In conclusion, diterpenes may be one of the lead mols. in the treatment of cancer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXms12nsrk%253D&md5=b8e2b667a67a0736a57ced8ea0a900b2
  45. 45
    Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3– 25,  DOI: 10.1016/S0169-409X(96)00423-1
    [Crossref], [CAS], Google Scholar
    45
    Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
    Lipinski, Christopher A.; Lombardo, Franco; Dominy, Beryl W.; Feeney, Paul J.
    Advanced Drug Delivery Reviews (1997), 23 (1-3), 3-25CODEN: ADDREP; ISSN:0169-409X. (Elsevier)
    A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is >500 and the calcd. Log P (CLogP) is >5. Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktlKlsQ%253D%253D&md5=405f70b0594d428f1275e1d56642cd3a
  46. 46
    Areche, C.; Schmeda-Hirschmann, G.; Theoduloz, C.; Rodríguez, J. A. Gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean Lamiaceae Sphacele chamaedryoides (Balbis) Briq. J. Pharm. Pharmacol. 2009, 61, 1689– 1697,  DOI: 10.1211/jpp.61.12.0015
    [Crossref], [PubMed], [CAS], Google Scholar
    46
    Gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean Lamiaceae Sphacele chamaedryoides (Balbis) Briq
    Areche, Carlos; Schmeda-Hirschmann, Guillermo; Theoduloz, Cristina; Rodriguez, Jaime A.
    Journal of Pharmacy and Pharmacology (2009), 61 (12), 1689-1697CODEN: JPPMAB; ISSN:0022-3573. (Pharmaceutical Press)
    The aim of this report was to isolate, identify and assess the gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean medicinal plant Sphacele chamaedryoides (Balbis) Briq. (Lamiaceae). The isolated compds. were identified by spectroscopic means. The gastroprotective effect of the compds. was studied on the HCl/EtOH-induced gastric lesions model in mice. The cytotoxicity of the compds. was assessed on human normal lung fibroblasts (MRC-5) and gastric adenocarcinoma cells (AGS). From the aerial parts of the plant, five phenolic and five p-quinone abietanes, the sesquiterpene spathulenol and two flavonoids were obtained. The main diterpene from the plant was carnosol. Lansoprazole at 20 mg/kg reduced gastric lesions by 64.7% (P < 0.01), being statistically similar to carnosol at doses of 10 and 20 mg/kg; the percent lesion redn. with 7 at 5 mg/kg was 49.3%. At a single oral dose of 5 mg/kg, the diterpenes bearing a p-quinone moiety - 6,7-dehydroroyleanone (1), royleanone (2), 7,20-epoxyroyleanone (3), taxoquinone (5) and horminone (6) - presented a gastroprotective effect of 54.4, 70.8, 65.0, 35.8 and 52.7%, resp. Of the C-7 hydroxy derivs., the activity was much lower for the 7β-OH isomer. The phenolic diterpenes 7 and 7-oxo-11,12,14-trihydroxy-8,11,13-abietatrien-20-al (8) inhibited gastric lesions by 49.3 and 53.0%, resp. Royleanone (2), 7,20-epoxyroyleanone (3), horminone (6), 8 and spathulenol proved to be cytotoxic with IC50 values in the range of 11-67 μM. The selective cytotoxicity of compds. 1 (IC50: 61 and 366 μM) and 5 (IC50: 310 and 27 μM) against AGS cells and fibroblasts, resp., merit addnl. studies. All the abietanes obtained from S. chamaedryoides present either one or two phenolic OH groups, a quinone system, or both. Several compds. present in the plant showed higher gastroprotective effect than lansoprazole. The cytotoxic effect of most compds. was found at fairly high concns. and lacked cell specificity. Further studies are required using different tumor cell lines and viability/proliferation assays to assess the specificity of the isolated compds. The selective cytotoxicity of compds. 1 and 5 against AGS cells and fibroblasts, resp., merit addnl. studies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXitFGqs70%253D&md5=2518d9811d058161c294b36ae4e8c32f
  47. 47
    Kusumoto, N.; Aburai, N.; Ashitani, T.; Takahashi, K.; Kimura, K.-i. Pharmacological prospects of oxygenated abietane-type diterpenoids from Taxodium distichum cones. Adv. Biol. Chem. 2014, 4, 109– 115,  DOI: 10.4236/abc.2014.42015
    [Crossref], [CAS], Google Scholar
    47
    Pharmacological prospects of oxygenated abietane-type diterpenoids from Taxodium distichum cones
    Kusumoto, Norihisa; Aburai, Nobuhiro; Ashitani, Tatsuya; Takahashi, Koetsu; Kimura, Ken-ichi
    Advances in Biological Chemistry (2014), 4 (2), 109-115, 7 pp.CODEN: ABCDAS; ISSN:2162-2191. (Scientific Research Publishing, Inc.)
    Eight naturally occurring diterpenoids, including 6,7-dehydroroyleanone, taxodal, taxodione, salvinolone, 14-deoxycoleon U, 5,6-dehydrosugiol, sandaracopimaric acid, and xanthoperol were isolated from Taxodium distichum cones and their biol. properties evaluated in vitro against six different biol. screening targets. Taxodione showed potent activity against a no. of different targets, and salvinolone and 14-deoxycoleon U showed remarkable inhibitory activities against prolyl oligopeptidase (POP) and 17α-hydroxylase/C17,20-lyase (CYP17), resp. These three compds. also showed strong cytotoxic activities against HL60 and K562 human leukemia cells. The structure-activity relationships of these compds. have also been considered. The findings in this study could lead to enhanced pharmacol. prospects for the natural abietane-type diterpenoids consisting in conifer cones.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgtbjK&md5=97b3d50fbac17187f9829f35775e229b
  48. 48
    Li, S.; Wang, P.; Deng, G.; Yuan, W.; Su, Z. Cytotoxic compounds from invasive giant salvinia (Salvinia molesta) against human tumor cells. Bioorg. Med. Chem. Lett. 2013, 23, 6682– 6687,  DOI: 10.1016/j.bmcl.2013.10.040
    [Crossref], [PubMed], [CAS], Google Scholar
    48
    Cytotoxic compounds from invasive giant salvinia (Salvinia molesta) against human tumor cells
    Li, Shiyou; Wang, Ping; Deng, Guangrui; Yuan, Wei; Su, Zushang
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (24), 6682-6687CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Giant salvinia (Salvinia molesta) is one of the most noxious invasive species in the world. Bioactivity-guided fractionation of ethanol ext. of giant salvinia led to the isolation of 50 compds. Of the six new compds. (1-6), salviniol (1) is a rare abietane diterpene with a new ferruginol-menthol coupled skeleton and both salviniside I (2) and salviniside II (3) are novel benzofuran glucose conjugates with unique 10-membered macrodiolide structures. Sixteen abietane diterpenes (1, 7-17, and 19-22) demonstrated in vitro activities against human tumor cells, and 7 and 8 showed selective cytotoxicity to tumor cells over normal cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCrtLbI&md5=d004b9c7624b9ee7c23f9a789a088663
  49. 49
    Jonathan, L. T.; Che, C.-T.; Pezzuto, J. M.; Fong, H. H. S.; Farnsworth, N. R. 7-O-Methylhorminone and other cytotoxic diterpene quinones from Lepechinia bullata. J. Nat. Prod. 1989, 52, 571– 575,  DOI: 10.1021/np50063a016
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    49
    7-O-methylhorminone and other cytotoxic diterpene quinones from Lepechinia bullata
    Jonathan, Lydia T.; Che, Chun Tao; Pezzuto, John M.; Fong, Harry H. S.; Farnsworth, Norman R.
    Journal of Natural Products (1989), 52 (3), 571-5CODEN: JNPRDF; ISSN:0163-3864.
    Three cytotoxic diterpene quinones, 6,7-dehydroroyleanone, horminone, and 7-O-methylhorminone, were isolated from an MeOH ext. of L. bullata after bioassay-directed fractionation and identified by 1H and 13C NMR, UV, IR, and mass spectroscopy and by comparison with authentic samples. 7-O-Methylhorminone is a new natural product.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltFags7w%253D&md5=9265cf793c3d78ab7382593bf93d8185
  50. 50
    Fernandes, A. S.; Serejo, J.; Gaspar, J.; Cabral, F.; Bettencourt, A. F.; Rueff, J.; Castro, M.; Costa, J.; Oliveira, N. G. Oxidative injury in V79 Chinese hamster cells: protective role of the superoxide dismutase mimetic MnTM-4-PyP. Cell Biol. Toxicol. 2010, 26, 91– 101,  DOI: 10.1007/s10565-009-9120-3
    [Crossref], [PubMed], [CAS], Google Scholar
    50
    Oxidative injury in V79 Chinese hamster cells: protective role of the superoxide dismutase mimetic MnTM-4-PyP
    Fernandes, Ana S.; Serejo, Joao; Gaspar, Jorge; Cabral, Fatima; Bettencourt, Ana F.; Rueff, Jose; Castro, Matilde; Costa, Judite; Oliveira, Nuno G.
    Cell Biology and Toxicology (2010), 26 (2), 91-101CODEN: CBTOE2; ISSN:0742-2091. (Springer)
    Oxidative cell injury could be induced by different reactive oxygen species (ROS) operating in multiple pathways. The present work is focused on three different models of oxidative stress: the xanthine/xanthine oxidase system (XXO), an extracellular superoxide anion generator; tert-butylhydroperoxide (TBHP), an analog of lipid hydroperoxides; and doxorubicin (Dox), an anticancer drug. Superoxide and peroxyl radicals, among other ROS, could be effectively scavenged by MnTM-4-PyP, a polyfunctional catalytic antioxidant. In this report, we have addressed the role of MnTM-4-PyP on the protection against the cytotoxicity induced by the three aforementioned oxidants. The effect of MnTM-4-PyP (0.1-100 μM) was evaluated in V79 fibroblasts using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide redn. and the crystal violet assays, as well as the mitotic index. Also, the generation of intracellular ROS was studied by the fluorescent probe dihydroethidium. MnTM-4-PyP has shown significant protective effects against the cytotoxicity of XXO and TBHP, increasing the cell viability in approx. 40% and reducing the intracellular level of ROS. However, no considerable protection occurred against Dox. The three oxidants caused a mitotic index redn. that was not altered by MnTM-4-PyP. In summary, MnTM-4-PyP appears to be a promising agent for the protection against oxidative injury. However, it has shown differential responses, reinforcing the need to study different exptl. models for the adequate evaluation of its potentialities as a catalytic antioxidant.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXis1eht78%253D&md5=0136924d1d14c68be73bbcb579591730
  51. 51
    Guerreiro, P. S.; Fernandes, A. S.; Costa, J. G.; Castro, M.; Miranda, J. P.; Oliveira, N. G. Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells. Mutat. Res. 2013, 757, 140– 147,  DOI: 10.1016/j.mrgentox.2013.08.003
    [Crossref], [PubMed], [CAS], Google Scholar
    51
    Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells
    Guerreiro, Patricia S.; Fernandes, Ana Sofia; Costa, Joao G.; Castro, Matilde; Miranda, Joana P.; Oliveira, Nuno G.
    Mutation Research, Genetic Toxicology and Environmental Mutagenesis (2013), 757 (2), 140-147CODEN: MRGMFI; ISSN:1383-5718. (Elsevier B.V.)
    Pharmacol. inhibition of DNA repair is a promising approach to increase the effectiveness of anticancer drugs. The chemotherapeutic drug doxorubicin (Dox) may act, in part, by causing oxidative DNA damage. The base excision repair (BER) pathway effects the repair of many DNA lesions induced by reactive oxygen species (ROS). Methoxyamine (MX) is an indirect inhibitor of apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional BER protein. We have evaluated the effects of MX on the cytotoxicity and genotoxicity of Dox in MDA-MB-231 metastatic breast cancer cells. MX has little effects on the viability and proliferation of Dox-treated cells. However, as assessed by the cytokinesis-block micronucleus assay (CBMN), MX caused a significant 1.4-fold increase (P < 0.05) in the frequency of micronucleated binucleated cells induced by Dox, and also altered the distribution of the nos. of micronuclei. The fluorescence probe dihydroethidium (DHE) indicated little prodn. of ROS by Dox. Overall, our results suggest differential outcomes for the inhibition of APE1 activity in breast cancer cells exposed to Dox, with a sensitizing effect obsd. for genotoxicity but not for cytotoxicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVOntrbJ&md5=ded80757ad199b27434232adbe737f66
  52. 52
    Pereira, P.; Bernardo-Gil, M. G.; Cebola, M. J.; Mauricio, E.; Romano, A. Supercritical fluid extracts with antioxidant and antimicrobial activities from myrtle (Myrtus communis L.) leaves. Response surface optimization. J. Supercrit. Fluids 2013, 83, 57– 64,  DOI: 10.1016/j.supflu.2013.08.010
    [Crossref], [CAS], Google Scholar
    52
    Supercritical fluid extracts with antioxidant and antimicrobial activities from myrtle (Myrtus communis L.) leaves. Response surface optimization
    Pereira, Paula; Bernardo-Gil, M. Gabriela; Cebola, M. Joao; Mauricio, Elisabete; Romano, Anabela
    Journal of Supercritical Fluids (2013), 83 (), 57-64CODEN: JSFLEH; ISSN:0896-8446. (Elsevier B.V.)
    Supercrit. Fluid Extn. (SFE) was used to obtain myrtle leaf exts., and to study the antioxidant capacity (AOC) and in vitro antimicrobial activity of those exts. To optimize the SFE operational conditions, the response surface methodol. (RSM) was adopted. The parameters studied were: pressure (P), within the range 10 to 30 MPa; temp. (T), between 35 and 60 and supercrit. carbon dioxide (SCCO2) flow rate (Q) within the range 0.15 to 0.45 kg h-1. The results show a good fit to the proposed model and the optimal conditions obtained (23 MPa, 45, and SCCO2 flow rate of 0.3 kg h-1) were within the exptl. range. The predicted values agreed with exptl. ones, thus indicating the suitability of the RSM model for the optimization of the extn. conditions being investigated. With those values remaining const., ethanol as a co-solvent was then studied. There was an obsd. rise in AOC as the amt. of ethanol increased, within the range studied (0-30% ethanol). The ext. with the highest AOC was tested for its antimicrobial activity against gram-pos. and gram-neg. bacteria. The min. inhibitory concn. (MIC) values obtained showed significant inhibitory effect against gram-pos. bacteria.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yitLbM&md5=5b048d3faf72f168b9dc3afaa9620186
  53. 53
    ICH Harmonised Tripartite Guideline Q2(R1). Validation of Analytical Procedures: Text and Methodology. In International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; European Medicines Agency: Chicago, IL, 2005.
    Google Scholar
    There is no corresponding record for this reference.
  54. 54
    Leão, M.; Soares, J.; Gomes, S.; Raimundo, L.; Ramos, H.; Bessa, C.; Queiroz, G.; Domingos, S.; Pinto, M.; Inga, A.; Cidade, H.; Saraiva, L. Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction. Life Sci. 2015, 142, 60– 65,  DOI: 10.1016/j.lfs.2015.10.015
    [Crossref], [PubMed], [CAS], Google Scholar
    54
    Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
    Leao, Mariana; Soares, Joana; Gomes, Sara; Raimundo, Liliana; Ramos, Helena; Bessa, Claudia; Queiroz, Gloria; Domingos, Sofia; Pinto, Madalena; Inga, Alberto; Cidade, Honorina; Saraiva, Lucilia
    Life Sciences (2015), 142 (), 60-65CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
    Chalcones are naturally occurring compds. with recognized anticancer activity. It was recently shown that the O-prenyl deriv. (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumor cells compared to its precursor. With this study, we aimed to investigate the mol. mechanism underlying the improved tumor cytotoxicity of prenylchalcone 2. The impact of chalcones 1 and 2 on p53-MDM2 interaction was investigated using yeast growth-inhibitory and p53 transactivation assays. Their tumor growth-inhibitory effects were assessed on human colon adenocarcinoma HCT116 cell lines with wild-type p53 and its p53-null deriv., followed by anal. of cell cycle and apoptosis. In tumor cells, the activation of a mitochondrial pathway was checked by anal. of reactive oxygen species generation, Bax mitochondrial translocation and cytochrome c release. Addnl., the up-regulation of p53 transcriptional activity was investigated through Western blot anal. of p53 target expression levels, and the disruption of the p53-MDM2 interaction was confirmed by co-immunopptn. The potent cell tumor growth-inhibitory activity of prenylchalcone 2 was assocd. with the activation of a p53 pathway involving cell cycle arrest and a mitochondria-dependent apoptosis. Furthermore, a correlation between the distinct cytotoxicity of chalcones 1 and 2 and their ability to disrupt the p53-MDM2 interaction was established. This work shows that prenylation is a determinant factor for the enhancement of chalcones tumor cytotoxicity by improving their ability to disrupt the p53-MDM2 interaction. Prenylchalcone 2 represents a starting basis for the design of new p53-MDM2 interaction inhibitors with improved antitumor properties.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslSjsbbM&md5=0a41db8b36c977761c6d98b31f0aecfc
  55. 55
    Soares, J.; Pereira, N. A. L.; Monteiro, Â.; Leão, M.; Bessa, C.; dos Santos, D. J. V. A.; Raimundo, L.; Queiroz, G.; Bisio, A.; Inga, A.; Pereira, C.; Santos, M. M. M.; Saraiva, L. Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction. Eur. J. Pharm. Sci. 2015, 66, 138– 147,  DOI: 10.1016/j.ejps.2014.10.006
    [Crossref], [PubMed], [CAS], Google Scholar
    55
    Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction
    Soares, Joana; Pereira, Nuno A. L.; Monteiro, Angelo; Leao, Mariana; Bessa, Claudia; dos Santos, Daniel J. V. A.; Raimundo, Liliana; Queiroz, Gloria; Bisio, Alessandra; Inga, Alberto; Pereira, Clara; Santos, Maria M. M.; Saraiva, Lucilia
    European Journal of Pharmaceutical Sciences (2015), 66 (), 138-147CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous neg. regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams and the evaluation of their biol. effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compds. 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The mol. mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53+/+) and in its isogenic deriv. without p53 (HCT116 p53-/-). Indeed, using these cells, we demonstrated that oxazoloisoindolinone 3a exhibited a p53-dependent in vitro antitumor activity through induction of G0/G1-phase cell cycle arrest and apoptosis. The selective activation of a p53-apoptotic pathway by oxazoloisoindolinone 3a was further supported by the occurrence of PARP cleavage only in p53-expressing HCT116 cells. Moreover, oxazoloisoindolinone 3a led to p53 protein stabilization and to the up-regulation of p53 transcriptional activity with increased expression levels of several p53 target genes, as p21(WAF1/CIP1), MDM2, BAX and PUMA, in p53+/+ but not in p53-/- HCT116 cells. Addnl., the ability of oxazoloisoindolinone 3a to block the p53-MDM2 interaction in HCT116 p53+/+ cells was confirmed by co-immunopptn. Finally, the mol. docking anal. of the interactions between the synthesized compds. and MDM2 revealed that oxazoloisoindolinone 3a binds to MDM2. Altogether, this work adds, for the first time, the oxazoloisoindolinone scaffold to the list of chemotypes activators of a wild-type p53-pathway with promising antitumor activity. Moreover, it may open the way to the development of a new class of p53-MDM2 interaction inhibitors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslKjtrrP&md5=5bb41ff3e1afbd46b39f8f48569c2dbc
  56. 56
    Fischedick, J. T.; Pesic, M.; Podolski-Renic, A.; Bankovic, J.; de Vos, R. C. H.; Perić, M.; Todorović, S.; Tanic, N. Cytotoxic activity of sesquiterpene lactones from Inula britannica on human cancer cell lines. Phytochem. Lett. 2013, 6, 246– 252,  DOI: 10.1016/j.phytol.2013.02.006
    [Crossref], [CAS], Google Scholar
    56
    Cytotoxic activity of sesquiterpene lactones from Inula britannica on human cancer cell lines
    Fischedick, Justin T.; Pesic, Milica; Podolski-Renic, Ana; Bankovic, Jasna; de Vos, Ric C. H.; Peric, Marija; Todorovic, Sladjana; Tanic, Nikola
    Phytochemistry Letters (2013), 6 (2), 246-252CODEN: PLHEBK; ISSN:1874-3900. (Elsevier B.V.)
    Five new sesquiterpene lactones (1-5) were isolated from Inula britannica collected in the wild from Serbia along with five known compds. (6-10). Sesquiterpene lactones were isolated using centrifugal partition chromatog. followed by combination of flash chromatog. and semi-preparative HPLC. Isolated compds. were screened for cytotoxic activity on four different human cancer cell lines and their multi-drug resistant counterparts, as well as on normal human keratinocytes. Sesquiterpene lactones showed similar cytotoxic activity toward drug sensitive and drug resistant cancer cell lines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntV2hsbk%253D&md5=15f881de1d9d40babe98af6ec26ad12f

Cited By

This article is cited by 2 publications.

  1. Vera M. S. Isca, Ricardo J. Ferreira, Catarina Garcia, Carlos M. Monteiro, Jelena Dinic, Suvi Holmstedt, Vânia André, Milica Pesic, Daniel J. V. A. dos Santos, Nuno R. Candeias, Carlos A. M. Afonso, Patrícia Rijo. Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors. ACS Medicinal Chemistry Letters 2020, 11 (5) , 839-845. https://doi.org/10.1021/acsmedchemlett.9b00642
  2. Nuno Saraiva, João G. Costa, Catarina Reis, Nuno Almeida, Patrícia Rijo, Ana Sofia Fernandes. Anti-Migratory and Pro-Apoptotic Properties of Parvifloron D on Triple-Negative Breast Cancer Cells. Biomolecules 2020, 10 (1) , 158. https://doi.org/10.3390/biom10010158

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Chemical structure of the major components in P. madagascariensis extracts: rosmarinic acid (1), 6β,7α-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. HPLC chromatogram showing the decomposition of coleon U (5) to coleon U quinone (6).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Proposed structure–activity relationships for 6,7,12-substituted royleanone-type abietane diterpenes based on data from Table 4.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 56 other publications.

    1. 1
      Lukhoba, C. W.; Simmonds, M. S. J.; Paton, A. J. Plectranthus: a review of ethnobotanical uses. J. Ethnopharmacol. 2006, 103, 1– 24,  DOI: 10.1016/j.jep.2005.09.011
      [Crossref], [PubMed], [CAS], Google Scholar
      1
      Plectranthus: a review of ethnobotanical uses
      Lukhoba Catherine W; Simmonds Monique S J; Paton Alan J
      Journal of ethnopharmacology (2006), 103 (1), 1-24 ISSN:0378-8741.
      Plectranthus is a large and widespread genus with a diversity of ethnobotanical uses. The genus is plagued with numerous nomenclatural disharmonies that make it difficult to collate accurate data on the uses. The aim of this review is to gather together all ethnobotanical information on Plectranthus and to map the data onto the most up-to-date phylogenetic classification in order to see if there are similar uses among related species and hence provide a framework for the prediction and exploration of new uses of species. The uses of 62 species of Plectranthus were mapped onto a current phylogeny based on DNA sequence data. The phylogeny reveals two major Clades, 1 and 2. The members of Clade 1 (corresponding to the formally recognized genus Coleus) were richer in number and diversity of uses than members of Clade 2 (comprising the remaining species of Plectranthus). The high incidence of synonymy can lead to problems in uncovering a species' ethnobotanical profile. About 30% of all citations of Plectranthus use a synonym and most of the synonyms are attributed to 10 of the most used species, 9 of which are in Clade 1. Members of the 'Coleus' Clade are the most studied group both taxonomically and economically. The higher incidence of study may be as a result of the higher diversity of uses and the fact that species in Clade 1, such as Plectranthus barbatus, Plectranthus amboinicus and Plectranthus mollis, are geographically more widespread than those in Clade 2. Plectranthus species in Clade 1 are frequently used as medicines and are used to treat a range of ailments, particularly digestive, skin, infective and respiratory problems. Plectranthus used as foods, flavours, fodder and materials are also mostly found in Clade 1. Monoterpenoids, sesquiterpenoids, diterpenoids and phenolics have been reported in species of Plectranthus. The abietane diterpenoids are the most diverse of the diterpenoids isolated from species of Plectranthus. The labdane diterpenoid, forskolin, occurs in Plectranthus barbatus and could explain some of the traditional uses of this species. This review highlights the fact that not enough is known about the chemistry of other species of Plectranthus to explain their traditional uses.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnjtVajtg%253D%253D&md5=2cfd3b10a293029e1217a2ba4e4b025d
    2. 2
      Gaspar-Marques, C.; Rijo, P.; Simões, M. F.; Duarte, M. A.; Rodríguez, B. Abietanes from Plectranthus grandidentatus and P. hereroensis against methicillin- and vancomycin-resistant bacteria. Phytomedicine 2006, 13, 267– 271,  DOI: 10.1016/j.phymed.2005.06.002
      [Crossref], [PubMed], [CAS], Google Scholar
      2
      Abietanes from Plectranthus grandidentatus and P. hereroensis against methicillin- and vancomycin-resistant bacteria
      Gaspar-Marques, C.; Rijo, P.; Simoes, M. F.; Duarte, M. A.; Rodriguez, B.
      Phytomedicine (2006), 13 (4), 267-271CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
      The antimicrobial activity of 10 natural abietanes isolated from Plectranthus grandidentatus and P. hereroensis acetonic ext. was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). The results revealed that the most active diterpenes were coleon U (1), 7α-acetoxy-6β-hydroxyroyleanone (2) and horminone (3). Min. inhibitory concn. (MIC) values ranging 0.98-15.63 μg/mL were obtained for MRSA clin. strains, and MIC values of 15.63 and 31.25 μg/mL were obtained for VRE clin. strains. Some structure-activity relationships are emphasized.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFyltb0%253D&md5=a60ee336e13fac37ee516d20a7aab022
    3. 3
      Rijo, P.; Faustino, C.; Simões, M. F. Antimicrobial natural products from Plectranthus plants. In Microbial Pathogens and Strategies for Combating Them: Science, Technology and Education; Méndez-Vilas, A., Ed.; Formatex: Badajoz, 2013; pp 922– 931.
      Google Scholar
      There is no corresponding record for this reference.
    4. 4
      Rijo, P.; Simões, M. F.; Francisco, A. P.; Rojas, R.; Gilman, R. H.; Vaisberg, A. J.; Rodríguez, B.; Moiteiro, C. Antimycobacterial metabolites from Plectranthus: royleanone derivatives against Mycobacterium tuberculosis strains. Chem. Biodiversity 2010, 7, 922– 932,  DOI: 10.1002/cbdv.200900099
      [Crossref], [PubMed], [CAS], Google Scholar
      4
      Antimycobacterial metabolites from Plectranthus: Royleanone derivatives against Mycobacterium tuberculosis strains
      Rijo, Patricia; Simoes, M. Fatima; Francisco, A. Paula; Rojas, Rosario; Gilman, Robert H.; Vaisberg, Abraham J.; Rodriguez, Benjamin; Moiteiro, Cristina
      Chemistry & Biodiversity (2010), 7 (4), 922-932CODEN: CBHIAM; ISSN:1612-1872. (Verlag Helvetica Chimica Acta)
      The antimycobacterial activities of eight diterpenes, 1-8, isolated previously from Plectranthus and eleven esters, 9-19, of 7α-acetoxy-6β,12-dihydroxyabieta-8,12-diene-11,14-dione (5) were evaluated against the MTB strains H37Rv and MDR. Only diterpenoids with a quinone framework revealed anti-MTB activity. Abietane 5 and its 6,12-dibenzoyl, 12-methoxybenzoyl, 12-chlorobenzoyl, and 12-nitrobenzoyl esters, 9, 11, 12, and 13, resp., showed potent activities against the MDR strain with MIC values between 3.12 and 0.39 μg/mL. Cytotoxic activities towards 3T3 and Vero cells were also evaluated. Compd. 11, with the best selectivity index, may be a suitable lead for further chem. modifications. The complete structural elucidation of the new esters, 9-14, 16, 18, and 19, as well as the NMR data of known derivs. 15 and 17 are reported.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltVygtr8%253D&md5=02479678bab8c5f76bab9c629a2bf3ce
    5. 5
      Kubínová, R.; Pořízková, R.; Navrátilová, A.; Farsa, O.; Hanáková, Z.; Bačinská, A.; Cížek, A.; Valentová, M. Antimicrobial and enzyme inhibitory activities of the constituents of Plectranthus madagascariensis (Pers.) Benth. J. Enzyme Inhib. Med. Chem. 2014, 6366, 1– 4,  DOI: 10.3109/14756366.2013.848204
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    6. 6
      Falé, P. L.; Borges, C.; Madeira, P. J. A.; Ascensão, L.; Araújo, M. E. M.; Florêncio, M. H.; Serralheiro, M. L. M. Rosmarinic acid, scutellarein 4′-methyl ether 7-O-glucuronide and (16S)-coleon E are the main compounds responsible for the antiacetylcholinesterase and antioxidant activity in herbal tea of Plectranthus barbatus (“falso boldo”). Food Chem. 2009, 114, 798– 805,  DOI: 10.1016/j.foodchem.2008.10.015
      [Crossref], [CAS], Google Scholar
      6
      Rosmarinic acid, scutellarein 4'-methyl ether 7-O-glucuronide and (16S)-coleon E are the main compounds responsible for the antiacetylcholinesterase and antioxidant activity in herbal tea of Plectranthus barbatus ("falso boldo")
      Fale, Pedro L.; Borges, Carlos; Madeira, Paulo J. Amorim; Ascensao, Lia; Araujo, Maria Eduarda M.; Florencio, Maria Helena; Serralheiro, Maria Luisa M.
      Food Chemistry (2009), 114 (3), 798-805CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier B.V.)
      Plectranthus barbatus, known as "falso boldo" in Brazil, is used in herbal tea or cooked as a vegetable. Infusions and decoctions of leaves from P. barbatus were analyzed for their inhibition of acetylcholinesterase and their antioxidant activity. The decoction showed high inhibition activity (31% inhibition with 0.5 mg of ext./mL) and also high antioxidant activity (IC50 = 45.8 ± 0.5 μg of dry ext./mL in the DPPH test; IC50 = 69.8 ± 3.1 μg of dry ext./mL in the β-carotene-linoleic acid test). Rosmarinic acid, scutellarein 4'-Me ether 7-O-glucuronide and (16S)-coleon E were the main constituents identified. These compds. have antiacetylcholinesterase activity. Rosmarinic acid and the scutellarein deriv. have IC50 = 440 μg/mL and 1 mg/mL, resp. One milligram per mL of (16S)-coleon E showed 61% inhibition of the enzyme. Other Plectranthus species, P. eckloni, P. fruticosus, P. lanuginosus and P. verticillatus, were also analyzed and the results obtained correlated with the content in rosmarinic acid.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvFansLo%253D&md5=33d02dfb3a42de03f164564fc172ba2a
    7. 7
      Gurgel, A. P. A. D.; da Silva, J. G.; Grangeiro, A. R. S.; Oliveira, D. C.; Lima, C. M. P.; da Silva, A. C. P.; Oliveira, R. A. G.; Souza, I. A. In vivo study of the anti-inflammatory and antitumor activities of leaves from Plectranthus amboinicus (Lour.) Spreng (Lamiaceae). J. Ethnopharmacol. 2009, 125, 361– 363,  DOI: 10.1016/j.jep.2009.07.006
      [Crossref], [PubMed], [CAS], Google Scholar
      7
      In vivo study of the anti-inflammatory and antitumor activities of leaves from Plectranthus amboinicus (Lour.) Spreng (Lamiaceae)
      Gurgel Ana Pavla A Diniz; da Silva Jackeline G; Grangeiro Ana Ruth S; Oliveira Danielli C; Lima Cynthia M P; da Silva Aldo C P; Oliveira Rinalda A G; Souza Ivone A
      Journal of ethnopharmacology (2009), 125 (2), 361-3 ISSN:.
      ETHNOPHARMACOLOGICAL RELEVANCE: Plectranthus amboinicus (Lour.) Spreng is a medicinal specie often used in Brazil, especially in Northeast Region, for the treatment of several diseases including inflammations and cancer. AIM OF THE STUDY: To evaluate the anti-inflammatory and antitumor activities of the hydroalcoholic extract from leaves of P. amboinicus in an attempt to determine whether the medicinal uses are supported by pharmacological effects. MATERIALS AND METHODS: Anti-inflammatory activity was determined by carrageenan-induced paw edema method. The antitumor effect was evaluated in an in vivo experimental study, using the following tumors: Sarcoma-180 and Erlich ascite carcinoma. RESULTS: There were statistically significant decreases (p<.05) of edema paw in at the doses of 150, 250 and 350 mg/kg (i.p.) of the hydroalcoholic extract of P. amboinicus. Similarly, the administration of P. amboinicus at the doses of 100, 150, 250 and 350 mg/kg (i.p.) inhibited the growth of sarcoma-180 and Ehrlich ascite carcinoma tumors in mice. CONCLUSION: The results suggest that the hydroalcoholic extract of P. amboinicus possesses anti-inflammatory and antitumor activities, supporting the folk use of this medicinal specie.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrntFWgsg%253D%253D&md5=c8663592dfe721dc0fe45123cbe83501
    8. 8
      Minker, C.; Sheridan, H.; O’Meara, J.; Johnse, L. V.; Hook, I.; Lobstein, A.; Frankish, N. In vivo and in vitro evaluation of anti-inflammatory activity and cytotoxicity of extracts of seven Plectranthus species. Planta Med. 2007, 73, 074  DOI: 10.1055/s-2007-986856
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    9. 9
      Burmistrova, O.; Perdomo, J.; Simões, M. F.; Rijo, P.; Quintana, J.; Estévez, F. The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells. Phytomedicine 2015, 22, 1009– 1016,  DOI: 10.1016/j.phymed.2015.06.013
      [Crossref], [PubMed], [CAS], Google Scholar
      9
      The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells
      Burmistrova, Olga; Perdomo, Juan; Simoes, M. Fatima; Rijo, Patricia; Quintana, Jose; Estevez, Francisco
      Phytomedicine (2015), 22 (11), 1009-1016CODEN: PYTOEY; ISSN:0944-7113. (Elsevier GmbH)
      Abietane diterpenes have attracted much attention because they display a wide range of biol. activities, including antitumor activities. These compds. are the most diverse of the diterpenoids isolated from species of Plectranthus. Naturally occurring diterpene parvifloron D is the main phytochem. constituent of Plectranthus ecklonii. To examine the therapeutic potential of the plant, we evaluated whether parvifloron D displays cytotoxicity against human tumor cells.The cytotoxicity was analyzed by colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was evaluated by fluorescent microscopy, transmission electron microscopy, flow cytometric anal. of annexin V-FITC and propidium iodide-stained cells and DNA fragmentation. Protein expression and processing and release of mitochondrial proteins were analyzed by Western blot. Caspase activity was detd. using colorimetric substrates. The membrane potential and intracellular reactive oxygen species were detected by flow cytometry.Parvifloron D displays strong cytotoxic properties against leukemia cells (HL-60, U-937, MOLT-3 and K-562) and in particular P-glycoprotein-overexpressing K-562/ADR cells, but has only weak cytotoxic effects on peripheral blood mononuclear cells (PBMCs). Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to parvifloron D-induced cytotoxicity. Growth inhibition of HL-60 cells that was triggered by parvifloron D was found to be caused by a rapid induction of apoptotic cell death. This apoptosis was prevented by the non-specific caspase inhibitor z-VAD-fmk, and by the selective caspase-9 inhibitor z-LEHD-fmk. Cell death induced by parvifloron D was found to be (i) assocd. with the dissipation of the mitochondrial membrane potential and the release of cytochrome c, (ii) amplified by inhibition of extracellular signal-regulated kinases (ERKs) 1/2 signaling and (iii) caused by a mechanism dependent on intracellular reactive oxygen species generation.Parvifloron D is a potent cytotoxic compd. against several human tumor cells and also a fast and potent apoptotic inducer in leukemia cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtF2itbvF&md5=24ffbf1637360ebd73364467a31add30
    10. 10
      Cerqueira, F.; Cordeiro-da-Silva, A.; Gaspar-Marques, C.; Simões, F.; Pinto, M. M. M.; Nascimento, M. S. J. Effect of abietane diterpenes from Plectranthus grandidentatus on T- and B-lymphocyte proliferation. Bioorg. Med. Chem. 2004, 12, 217– 223,  DOI: 10.1016/j.bmc.2003.10.006
      [Crossref], [PubMed], [CAS], Google Scholar
      10
      Effect of abietane diterpenes from Plectranthus grandidentatus on T- and B-lymphocyte proliferation
      Cerqueira, F.; Cordeiro-Da-Silva, A.; Gaspar-Marques, C.; Simoes, F.; Pinto, M. M. M.; Nascimento, M. S. J.
      Bioorganic & Medicinal Chemistry (2004), 12 (1), 217-223CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
      Five known abietane diterpenes of the royleanone and coleon type, namely, fatty acid esters of 7α-acyloxy-6β-hydroxyroyleanone (1), grandidone A (2), 7α-acetoxy-6β-hydroxyroyleanone (3), 6β,7α-dihydroxyroyleanone (4) and coleon U (5), isolated from Plectranthus grandidentatus, were evaluated for their effect on the proliferation of human lymphocytes induced by the mitogen PHA. All except 4, showed a dose-dependent suppressor effect, with 3 yielding the most potent antiproliferative activity, followed by 5. These two compds., that represent diterpenes of the royleanone and coleon type resp., were also shown to be potent inhibitors of mouse splenocyte proliferation induced by ConA or LPS mitogens. However, the sensitivity of ConA-stimulated splenocytes to their suppressive effect was higher, suggesting a preferential inhibition of T-lymphocyte proliferation. The antiproliferative activity of 3 seemed to be exerted without affecting the expression of the lymphocyte activation marker CD69. On the contrary, 5 was shown to reduce the expression of CD69 of TCD8+ and B-cells, suggesting a relationship between its antiproliferative effect and the expression of this early marker of activation on these cell populations. The capacity of 5 to induce apoptosis on ConA-stimulated splenocytes could also be related with its antiproliferative activity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVSjtLfL&md5=3f3d1738aeb903d23463a145f4ffbd65
    11. 11
      Marques, C. G.; Pedro, M.; Simões, M. F. A.; Nascimento, M. S. J.; Pinto, M. M. M.; Rodríguez, B. Effect of abietane diterpenes from Plectranthus grandidentatus on the growth of human cancer cell lines. Planta Med. 2002, 68, 839– 840,  DOI: 10.1055/s-2002-34407
      [Crossref], [PubMed], [CAS], Google Scholar
      11
      Effect of abietane diterpenes from plectranthus grandidentatus on the growth of human cancer cell lines
      Marques, Cristina Caspar; Pedro, Madalena; Simoes, M. Fatima A.; Nascimento, Maria Sao Jose; Pinto, Madalena M. M.; Rodriguez, Benjamin
      Planta Medica (2002), 68 (9), 839-840CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
      Five known abietane diterpenes, fatty acid esters of 7α-acyloxy-6β-hydroxyroyleanone (1), grandidone A (2), 7α-acetoxy-6β-hydroxyroyleanone (3), 6β,7α-dihydroxyroyleanone (4), and coleon U (5), isolated from Plectranthus grandidentatus Gurke, were evaluated for their in vitro antiproliferative activity against five human cancer cell lines MCF-7, NCI-H460, SF-268, TK-10, and UACC-62. Coleon U (5) exhibited the strongest effect among all the assayed compds. The abietane 3 revealed also a strong inhibitory effect while diterpenes 2 and 4 inhibited only slightly the growth of all cancer cell lines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotVGns7c%253D&md5=e397eaacc48a2997b669c5591b28ceb6
    12. 12
      Saeed, M. E. M.; Meyer, M.; Hussein, A.; Efferth, T. Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells. J. Ethnopharmacol. 2016, 186, 209– 223,  DOI: 10.1016/j.jep.2016.04.005
      [Crossref], [PubMed], [CAS], Google Scholar
      12
      Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells
      Saeed, Mohamed E. M.; Meyer, Marion; Hussein, Ahmed; Efferth, Thomas
      Journal of Ethnopharmacology (2016), 186 (), 209-223CODEN: JOETD7; ISSN:0378-8741. (Elsevier Ireland Ltd.)
      Traditional medicine plays a major role for primary health care worldwide. Cancer belongs to the leading disease burden in industrialized and developing countries. Successful cancer therapy is hampered by the development of resistance towards established anticancer drugs. In the present study, we investigated the cytotoxicity of 29 exts. from 26 medicinal plants of South-Africa against leukemia cell lines, most of which are used traditionally to treat cancer and related symptoms. We have investigated the plant exts. for their cytotoxic activity towards drug-sensitive parental CCRF-CEM leukemia cells and their multidrug-resistant P-glycoprotein-overexpressing subline, CEM/ADR5000 by means of the resazurin assay. A panel of 60 NCI tumor cell lines have been investigated for correlations between selected phytochems. from medicinal plants and the expression of resistance-conferring genes (ABC-transporters, oncogenes, tumor suppressor genes). Seven exts. inhibited both cell lines (Acokanthera oppositifolia, Hypoestes aristata, Laurus nobilis, Leonotis leonurus, Plectranthus barbatus, Plectranthus ciliates, Salvia apiana). CEM/ADR5000 cells exhibited a low degree of cross-resistance (3.35-fold) towards the L. leonurus ext., while no cross-resistance was obsd. to other plant exts., although CEM/ADR5000 cells were highly resistant to clin. established drugs. The log10IC50 values for two out of 14 selected phytochems. from these plants (acovenoside A and ouabain) of 60 tumor cell lines were correlated to the expression of ABC-transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS) and tumor suppressors (TP53). Sensitivity or resistance of the cell lines were not statistically assocd. with the expression of these genes, indicating that multidrug-resistant, refractory tumors expressing these genes may still respond to acovenoside A and ouabain. The bioactivity of South African medicinal plants may represent a basis for the development of strategies to treat multidrug-resistant tumors either by phytotherapeutic approaches with whole plant prepns. or by classical drug development with isolated compds. such as acovenoside A or ouabain.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsVeis7w%253D&md5=e4edb6e652bc5b788d34f71369a7116b
    13. 13
      Hasibuan, P. A. Z.; Rosidah; Ilyas, S.; Nasution, M. P. Antioxidant and cytotoxic activities of Plectranthus amboinicus (Lour.) Spreng. extracts. Int. J. Pharm. Teach. Pract. 2013, 4, 755– 758
      Google Scholar
      There is no corresponding record for this reference.
    14. 14
      Ramalakshmi, P.; Subramanian, N.; Saravanan, R.; Mohanakrishnan, H.; Muthu, M. Anticancer effect of Coleus amboinicus (Karpporavalli) on human lung cancer cell line (A549). Int. J. Dev. Res. 2014, 4, 2442– 2449
      Google Scholar
      There is no corresponding record for this reference.
    15. 15
      Arcanjo, D. D. R.; Albuquerque, A. C. M.; Melo-Neto, B.; Santana, L. C. L. R.; Medeiros, M. G. F.; Citó, A. M. G. L. Bioactivity evaluation against Artemia salina Leach of medicinal plants used in Brazilian Northeastern folk medicine. Braz. J. Biol. 2012, 72, 505– 509,  DOI: 10.1590/S1519-69842012000300013
      [Crossref], [PubMed], [CAS], Google Scholar
      15
      Bioactivity evaluation against Artemia salina Leach of medicinal plants used in Brazilian Northeastern folk medicine
      Arcanjo D D R; Albuquerque A C M; Melo-Neto B; Santana L C L R; Medeiros M G F; Cito Amgl
      Brazilian journal of biology = Revista brasleira de biologia (2012), 72 (3), 505-9 ISSN:.
      The brine shrimp (Artemia salina Leach) lethality bioassay offers an advantage in standardization and quality control of botanical products. This test is well correlated with antitumor activity (cytotoxicity) and can be used to monitor the activity of bioactive natural products. This paper reports the bioactivity of ethanol extracts from seven medicinal plants from the Northeast of Brazil (Acmella uliginosa, Ageratum conyzoides, Eugenia uniflora, Plectranthus neochilus, Moringa oleifera, Justicia pectoralis and Equisetum sp.) against Artemia salina. Biological activity was evaluated for extracts at 1, 10, 100, and 1000 μg/mL in triplicate, and the mean lethal concentration values (LC50) were obtained by probit analysis. The species Acmella uliginosa showed the highest bioactivity, and its flower extract was more active than its leaf extract.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bot1ansg%253D%253D&md5=56a6c8afeb0eb69af2b7e9291b3918c5
    16. 16
      Borges, G. A.; Ferreira, J. F.; Elias, S. T.; Guerra, E. N. S.; Silveira, D.; Simeoni, L. A. Cytotoxic effect of Plectranthus neochilus extracts in head and neck carcinoma cell lines. Afr. J. Pharm. Pharmacol. 2016, 10, 157– 163,  DOI: 10.5897/AJPP2015.4355
      [Crossref], [CAS], Google Scholar
      16
      Cytotoxic effect of Plectranthus neochilus extracts in head and neck carcinoma cell lines
      Borges, Gabriel Alvares; Ferreira, Juliana Freitas; Elias, Silvia Taveira; Guerra, Eliete Neves Silva; Silveira, Damaris; Simeoni, Luiz Alberto
      African Journal of Pharmacy and Pharmacology (2016), 10 (10), 157-163CODEN: AJPPHM; ISSN:1996-0816. (Academic Journals)
      Following a tendency of studying the potential effects of plant exts. to cancer, this study aimed to evaluate in vitro the cytotoxic activity of Plectranthus neochilus (PN) exts. and its fractions in head and neck squamous cell carcinoma (HNSCC) cell lines and assess their tumor specificity. MTT assay was conducted with two HNSCC cell lines, FaDu (hypopharynx carcinoma) and SCC-25 (tongue carcinoma), one keratinocyte (HaCat) and one fibroblast (L929) cell line. Two PN leaf crude exts., one ethanolic (E) and one hexanic (H), and their nine fractions were tested. A dose-response curve was performed with hexane PNH fraction and a tumor specificity index (TSI) was calcd. For all cell lines studied, almost all exts. and fractions resulted in cell viability lower than 50%. Hexane and methanol PNH fractions were exceptions, causing a significantly low viability in SCC-25 (17.16 and 34.53%, resp.), but higher than 50% in FaDu, HaCat and L929. The dose-response curve with hexane PNH fraction resulted in a CC50 of 540.9 μg/mL for FaDu, 550 μg/mL for L929, 762.1 μg/mL for HaCat and 274.2 μg/mL for SCC-25. The TSI L929/FaDu was 1.01, HaCat/FaDu was 1.40, L929/SCC-25 was 2.00 and HaCat/SCC-25 was 2.77. TSIs indicate its specificity for tongue carcinoma cells, when compared to fibroblasts and keratinocytes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVyiurnK&md5=f89d87953053dc8e3a015a04390df493
    17. 17
      Agarwal, K. C.; Parks, R. E., Jr. Forskolin: a potential antimetastatic agent. Int. J. Cancer 1983, 32, 801– 804,  DOI: 10.1002/ijc.2910320622
      [Crossref], [PubMed], [CAS], Google Scholar
      17
      Forskolin: a potential antimetastatic agent
      Agarwal, Kailash C.; Parks, Robert E., Jr.
      International Journal of Cancer (1983), 32 (6), 801-4CODEN: IJCNAW; ISSN:0020-7136.
      The effect of forskolin [66575-29-9] on tumor-induced human platelet aggregation and pulmonary tumor colonization in mice was examd. Forskolin (2 μM) strongly inhibited B-16 F10 melanoma cell-induced human platelet aggregation. A single dose of forskolin (82 μg/mouse) administered i.p. 30 or 60 min prior to tail vein injection of cultured B16-F10 cells reduced tumor colonization in the lungs by >70%. Thus, forskolin could prove of value for the prevention of metastasis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtFCltQ%253D%253D&md5=90dd9b48eb6e747afe5b6ee630b42389
    18. 18
      McEwan, D. G.; Brunton, V. G.; Baillie, G. S.; Leslie, N. R.; Houslay, M. D.; Frame, M. C. Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res. 2007, 67, 5248– 5257,  DOI: 10.1158/0008-5472.CAN-07-0097
      [Crossref], [PubMed], [CAS], Google Scholar
      18
      Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4-Regulated Compartment via Effects on Phosphoinositide 3-Kinase
      McEwan, David G.; Brunton, Valerie G.; Baillie, George S.; Leslie, Nicholas R.; Houslay, Miles D.; Frame, Margaret C.
      Cancer Research (2007), 67 (11), 5248-5257CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cAMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G1 by inducing p27Kip1 and primes cells for apoptosis on addn. of rolipram. The effect of the low-dose forskolin/rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a crit. intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homolog, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concns. in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clin. development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVaitr8%253D&md5=022bebe0d7d6bc137110d1b2d1039be4
    19. 19
      Burmistrova, O.; Simões, M. F.; Rijo, P.; Quintana, J.; Bermejo, J.; Estévez, F. Antiproliferative activity of abietane diterpenoids against human tumor cells. J. Nat. Prod. 2013, 76, 1413– 1423,  DOI: 10.1021/np400172k
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19
      Antiproliferative Activity of Abietane Diterpenoids against Human Tumor Cells
      Burmistrova, Olga; Simoes, M. Fatima; Rijo, Patricia; Quintana, Jose; Bermejo, Jaime; Estevez, Francisco
      Journal of Natural Products (2013), 76 (8), 1413-1423CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was detd. against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids contg. an abietane skeleton including taxodone and taxodione, as well as the semisynthetic derivs. 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone, 7α-acetoxy-6β-(4-nitro)benzoyloxyroyleanone, and 7α-acetoxy-6β-butyryloxyroyleanone, were the most cytotoxic compds. for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to abietane diterpene-induced cytotoxicity. Studies performed on HL-60 cells indicated that growth inhibition triggered by compds. taxodone, 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone, 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone, and 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone was caused by induction of apoptosis. This was prevented by the nonspecific caspase inhibitor Z-VAD-FMK and, in the case of compds. 7α-acetoxy-6β-hydroxy-12-O-(4-methoxy)benzoylroyleanone and 7α-acetoxy-6β-hydroxy-12-O-(4-chloro)benzoylroyleanone, reduced by the selective caspase-8 inhibitor Z-IETD-FMK. Cell death induced by these abietane diterpenes was found to be assocd. with the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing factor), accompanied by dissipation of the mitochondrial membrane potential (ΔΨ), and modulated by inhibition of extracellular signal-regulated kinases signaling and the p38 mitogen-activated protein kinase pathway.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFeqsrbE&md5=6329ffd49138f45321e9241d44b00ce4
    20. 20
      Cowan, M. M. Plant products as antimicrobial agents. Clin. Microbiol. Rev. 1999, 12, 564– 582,  DOI: 10.1128/CMR.12.4.564
      [Crossref], [PubMed], [CAS], Google Scholar
      20
      Plant products as antimicrobial agents
      Cowan, Marjorie Murphy
      Clinical Microbiology Reviews (1999), 12 (4), 564-582CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
      A review with 253 refs. The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combining the Earth for phytochems. and "leads" which could be developed for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties. This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure and antimicrobial properties of phytochems. are also addressed. Since many of these compds. are currently available as unregulated botanical prepns. and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these prepns.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXntFSmsLc%253D&md5=278c87a12597ea390a55e963c04f6097
    21. 21
      Ladeiras, D.; Monteiro, C. M.; Pereira, F.; Reis, C. P.; Afonso, C. A. M.; Rijo, P. Reactivity of diterpenoid quinones: royleanones. Curr. Pharm. Des. 2016, 22, 1682– 1714,  DOI: 10.2174/1381612822666151211094521
      [Crossref], [PubMed], [CAS], Google Scholar
      21
      Reactivity of Diterpenoid Quinones: Royleanones.
      Ladeiras, Diogo; Monteiro, Carlos M.; Pereira, Filipe; Reis, Catarina P.; Afonso, Carlos A. M.; Rijo, Patricia
      Current Pharmaceutical Design (2016), 22 (12), 1682-1714CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      Naturally occurring abietane diterpenoids have been studied over the years and have shown to display a wide range of biol. activities. This review covers three main aspects of the abietane-type diterpenoids with hydroxy-p-quinone C ring, designated as royleanones. An overview of 1) the naturally occurrence, 2) chem. features and 3) the biol. activities of this abietane group of compds., including rearranged derivs., is here explained. Likewise, hemisynthetic and total synthetic procedures to obtain royleanones will be reviewed. Thus, the chem. of these bioactive compds. will be emphasized as well as their potential impact in the discovery of new macromol. targets and novel therapeutic drugs. This review contains about 190 refs. covering the years from 1962 to 2014 on royleanone studies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtVOlu74%253D&md5=d5a049e6f668211959cb7379e2e415ea
    22. 22
      Yulianto, W.; Andarwulan, N.; Giriwono, P. E.; Pamungkas, J. HPLC-based metabolomics to identify cytotoxic compounds from Plectranthus amboinicus (Lour.) Spreng against human breast cancer MCF-7cells. J. Chromatogr. B 2016, 1039, 28– 34,  DOI: 10.1016/j.jchromb.2016.10.024
      [Crossref], [PubMed], [CAS], Google Scholar
      22
      HPLC-based metabolomics to identify cytotoxic compounds from Plectranthus amboinicus (Lour.) Spreng against human breast cancer MCF-7Cells
      Yulianto, Wahid; Andarwulan, Nuri; Giriwono, Puspo Edi; Pamungkas, Joko
      Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2016), 1039 (), 28-34CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
      The objective of this study was to identify the active compds. in Plectranthus amboinicus (Lour.) Spreng which play a role to inhibit viability of breast cancer MCF-7 cells using HPLC-based metabolomics approach. Five fractions of the plant ext. were obsd. including ethanol, hexane, chloroform, Et acetate and water fraction. There were 45 HPLC chromatograms resulted from 5 fractions with 3 replications and 3 wavelengths detection. The chromatograms were compared to the data of IC50 from MTT assay of each fraction against human breast cancer MCF-7 cells using metabolomics. The OPLS anal. result promptly pointed towards a chloroform fraction at retention time of 40.16-41.28 min that has the greatest contribution to the cytotoxic activity. The data of mass spectra indicated that an abietane diterpene namely 7-acetoxy-6-hydroxyroyleanone was the main compd. that contributed to the cytotoxic activity. This metabolomics application method can be used as a quick preliminary guideline to uncover the most dominant compd. related to the bioactivity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslyjtL%252FF&md5=51aeb2e1bb1fd3264574c7185d964451
    23. 23
      Wellsow, J.; Grayer, R. J.; Veitch, N. C.; Kokubun, T.; Lelli, R.; Kite, G. C.; Simmonds, M. S. J. Insect-antifeedant and antibacterial activity of diterpenoids from species of Plectranthus. Phytochemistry 2006, 67, 1818– 1825,  DOI: 10.1016/j.phytochem.2006.02.018
      [Crossref], [PubMed], [CAS], Google Scholar
      23
      Insect-antifeedant and antibacterial activity of diterpenoids from species of Plectranthus
      Wellsow, Julia; Grayer, Renee J.; Veitch, Nigel C.; Kokubun, Tetsuo; Lelli, Roberto; Kite, Geoffrey C.; Simmonds, Monique S. J.
      Phytochemistry (Elsevier) (2006), 67 (16), 1818-1825CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
      Bio-assay guided fractionation of an acetone ext. of leaf material from Plectranthus saccatus Benth. resulted in the isolation of a beyerane diterpenoid. This compd., characterized by spectroscopic methods as ent-3β-(3-methyl-2-butenoyl)oxy-15-beyeren-19-oic acid, showed insect antifeedant activity against Spodoptera littoralis. Known quinonoid abietane diterpenoids obtained from new sources included a mixt. of the (4R,19R) and (4R,19S) diastereoisomers of coleon A from P. aff. puberulentus J. K. Morton, coleon A lactone from P. puberulentus J. K. Morton, and coleon U and coleon U quinone from P. forsteri Marginatus' Benth. These compds., and the crude acetone exts. from the leaf surfaces of 11 species of Plectranthus, were tested for antifeedant activity against S. littoralis, antibacterial activity against Bacillus subtilis and Pseudomonas syringae and antifungal activity against Cladosporium herbarum. The coleon A mixt. showed potent antifeedant activity against S. littoralis, whereas coleon U showed the greatest antimicrobial activity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XovVSiur0%253D&md5=517b076023480a04d7b925926cab8d2e
    24. 24
      Matias, D.; Pereira, F.; Nicolai, M.; Roberto, A.; Saraiva, N.; Fernandes, A. S.; Simões, M. F.; Lanza, A. D.; Reis, C. P.; Rijo, P. Abietane diterpenes from Plectranthus madagascariensis: a cytotoxicity screening. Planta Med. 2014, 80, P1L152,  DOI: 10.1055/s-0034-1394809
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    25. 25
      Miyase, T.; Rüedi, P.; Eugster, C. H. Diterpenoide Drüsenfarbstoffe aus Labiaten: Coleone U, V, W und 14-O-Formyl-coleon-V sowie 2 Royleanone aus Plectranthus myrianthus BRIQ.;cis- undtrans-A/B-6, 7-Dioxoroyleanon. Helv. Chim. Acta 1977, 60, 2770– 2779,  DOI: 10.1002/hlca.19770600830
      [Crossref], [CAS], Google Scholar
      25
      Diterpenoid leaf-gland pigments from Labiatae: coleons U, V, W, 14-O-formylcoleon V, and two royleanones from Plectranthus myrianthus Briq.; cis- and trans-A/B-6,7-dioxoroyleanone
      Miyase, Toshio; Ruedi, Peter; Eugster, Conrad Hans
      Helvetica Chimica Acta (1977), 60 (8), 2770-9CODEN: HCACAV; ISSN:0018-019X.
      From leaf-glands of the South-African P. myrianthus (Labiatae) the following diterpenoids were isolated and their structures established: coleon U, C20H26O5, I; coleon V, C20H26O5, II; coleon W, C22H28O8, III; 14-O-formyl-coleon V, C21H26O6, IV; 7α-formyloxy-6β-hydroxyroyleanone, C21H28O6; the already known 6β,7α-dihydroxyroyleanone and a dimeric abietane deriv. whose structure was not yet elucidated. This is the first record of a co-occurrence of coleons and royleanones in the same plant. In the course of chem. investigations of II and IV, the highly oxidized trans- and cis-A/B-6,7-dioxoroyleanones were obtained.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXhtVWmt78%253D&md5=9b9d283769dd663da8cd8333b75e58d0
    26. 26
      Mei, S.-X.; Jiang, B.; Niu, X.-M.; Li, M.-L.; Yang, H.; Na, Z.; Lin, Z.-W.; Li, C.-M.; Sun, H.-D. Abietane diterpenoids from Coleus xanthanthus. J. Nat. Prod. 2002, 65, 633– 637,  DOI: 10.1021/np0102049
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      26
      Abietane Diterpenoids from Coleus xanthanthus
      Mei, Shuang-Xi; Jiang, Bei; Niu, Xue-Mei; Li, Ma-Lin; Yang, Hui; Na, Zhi; Lin, Zhong-Wen; Li, Chao-Ming; Sun, Han-Dong
      Journal of Natural Products (2002), 65 (5), 633-637CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
      Eight new abietane diterpenoids, coleon U 11-acetate (1), 16-acetoxycoleon U 11-acetate (2), and xanthanthusins F-K (3-8), together with five known analogs, coleon U (9), 16-O-acetylcoleon C (10), coleon U-quinone (11), 8α,9α-epoxycoleon U-quinone (12), and xanthanthusin E (13), were isolated from the aerial parts of Coleus xanthanthus. The structures of 1-8 were elucidated on the basis of spectral methods. Compds. 1, 5, and 11-13 were evaluated for their cytotoxicity against K562 human leukemia cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XisVeksLc%253D&md5=3813ae7255496e2bb6ef8771bef22bdd
    27. 27
      Coutinho, I.; Pereira, G.; Simões, M. F.; Côrte-Real, M.; Gonçalves, J.; Saraiva, L. Selective activation of protein kinase C-δ and -ε by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U). Biochem. Pharmacol. 2009, 78, 449– 459,  DOI: 10.1016/j.bcp.2009.04.026
      [Crossref], [PubMed], [CAS], Google Scholar
      27
      Selective activation of protein kinase C-δ and -ε by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U)
      Coutinho, I.; Pereira, G.; Simoes, M. F.; Corte-Real, M.; Goncalves, J.; Saraiva, L.
      Biochemical Pharmacology (2009), 78 (5), 449-459CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
      6,11,12,14-Tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U) is a diterpene compd. isolated from Plectranthus grandidentatus with an antiproliferative effect on several human cancer cell lines. Herein, we studied the modulatory activity of coleon U on individual isoforms of the three protein kinase C (PKC) subfamilies, classical (cPKC-α and -βI), novel (nPKC-δ and -ε) and atypical (aPKC-ζ), using a yeast PKC assay. The results showed that, whereas the PKC activator phorbol-12-myristate-13-acetate (PMA) activated every PKC tested except aPKC, coleon U had no effect on aPKC and cPKCs. Besides, the effect of coleon U on nPKCs was higher than that of PMA. This revealed that coleon U was a potent and selective activator of nPKCs. The isoform-selectivity of coleon U for nPKC-δ and -ε was confirmed using an in vitro PKC assay. Most importantly, while PMA activated nPKCs inducing an isoform translocation from the cytosol to the plasma membrane and a G2/M cell cycle arrest, coleon U induced nPKCs translocation to the nucleus and a metacaspase- and mitochondrial-dependent apoptosis. This work therefore reconstitutes in yeast distinct subcellular translocations of a PKC isoform and the subsequent distinct cellular responses reported for mammalian cells. Together, our study identifies a new isoform-selective PKC activator with promising pharmacol. applications. Indeed, since coleon U has no effect on cPKCs and aPKC, recognized as anti-apoptotic proteins, and selectively induces an apoptotic pathway dependent on nPKC-δ and -ε activation, it represents a promising compd. for evaluation as an anti-cancer drug.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotFOlt70%253D&md5=2103d2bba7b9c1b304d4d6d57af90853
    28. 28
      Matias, D.; Bessa, C.; Simões, M. F.; Reis, C. P.; Saraiva, L.; Rijo, P. Natural products as lead protein kinase C modulators for cancer therapy. In Studies in Natural Products Chemistry: Bioactive Natural Products; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2016; pp 45– 79.
      Google Scholar
      There is no corresponding record for this reference.
    29. 29
      Hensch, M.; Rüedi, P.; Eugster, C. H. Horminon, Taxochinon und weitere Royleanone aus 2 abessinischenPlectranthus-Spezies (Labiatae). Helv. Chim. Acta 1975, 58, 1921– 1934,  DOI: 10.1002/hlca.19750580707
      [Crossref], [CAS], Google Scholar
      29
      Horminone, taxoquinone, and other royleanones obtained from two Abyssinian Plectranthus species (Labiatae)
      Hensch, Marcel; Ruedi, Peter; Eugster, Conrad H.
      Helvetica Chimica Acta (1975), 58 (7), 1921-34CODEN: HCACAV; ISSN:0018-019X.
      Royleanone (I, R=H, Z=H2), 6,7-dehydroroyleanone (II), horminone (I, R=H, Z= α-OH, β-H), taxoquinone (I, R = H, Z=α-H,β-OH), 6β,7α-dihydroxyroyleanone (I, R=OH, Z=α-OAc,β-H), and 7-oxoroyleanone (I, R=H, Z=O) were isolated from the leaves of 2 Plectranthus species and their structures detd. on the basis of their uv and NMR spectra and by chem. correlation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XksVCitw%253D%253D&md5=163fdf1206635c0aa890280218f63bdd
    30. 30
      Brits, G. J.; Selchau, J.; van Deuren, G. Indigenous Plectranthus (Lamiaceae) from South Africa as new flowering pot plants. In XX International Eucarpia Symposium, Section Ornamentals, Strategies for New Ornamentals-Part I; 2001, 165– 170.
      Google Scholar
      There is no corresponding record for this reference.
    31. 31
      Van Zyl, R. L.; Khan, F.; Edwards, T. J.; Drewes, S. E. Antiplasmodial activities of some abietane diterpenes from the leaves of five Plectranthus species. S. Afr. J. Sci. 2008, 104, 62– 64
      [CAS], Google Scholar
      31
      Antiplasmodial activities of some abietane diterpenes from the leaves of five Plectranthus species
      van Zyl, R. L.; Khan, F.; Edwards, T. J.; Drewes, S. E.
      South African Journal of Science (2008), 104 (1/2), 62-64CODEN: SAJSAR; ISSN:0038-2353. (Academy of Science of South Africa)
      Seven known abietane diterpenes were isolated from five Plectranthus species, namely P. hadiensis, P. lucidus, P. eckloni, P. purpuratus subsp. purpuratus and P. purpuratus subsp. tongaensis. The seven compds. were tested for their antiplasmodial activity and for their ability to inhibit β-haematin formation. Overall, they showed good activity (IC50 values ranging from 3.11 to 14.65 μM), with one compd. being 62% as effective as chloroquine in inhibiting β-haematin formation. However, the cytotoxicity profile indicated a low degree of specificity towards the malaria parasite. When combined with quinine, three compds. interacted in an additive manner whereas one interacted synergistically.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsFCgsLg%253D&md5=da766abebd9fb66935f6e8b541543f61
    32. 32
      Abdel-Mogib, M.; Albar, H. A.; Batterjee, S. M. Chemistry of the genus Plectranthus. Molecules 2002, 7, 271– 301,  DOI: 10.3390/70200271
      [Crossref], [CAS], Google Scholar
      32
      Chemistry of the genus Plectranthus
      Abdel-Mogib, M.; Albar, H. A.; Batterjee, S. M.
      Molecules [online computer file] (2002), 7 (2), 271-301CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)
      A review. This review presents the phytochem. constituents of the genus Plectranthus reported up to 1999. Only a tetrameric deriv. of caffeic acid was isolated from P. japonicus, but a group of long-chain alkylphenols, of possible taxonomic significance in the genus, was also isolated. As a genus of the subfamily Nepetoideae, Plectranthus is free from iridoid glycosides and rich in essential oil (i.e. > 0.5% volatile oil on a dry wt. basis). Diterpenoids are the more common secondary metabolites in Plectranthus. The majority of them are highly modified abietanoids. This seems to be similar to the pattern of diterpenoids obsd. for Salvia, but no clerodane diterpenoids were found in Plectranthus.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjs1Krurs%253D&md5=f734b6aaf81ac2dd57f5b7a6ce1d60b9
    33. 33
      Rijo, P.; Matias, D.; Fernandes, A. S.; Simões, M. F.; Nicolai, M.; Reis, C. P. Antimicrobial plant extracts encapsulated into polymeric beads for potential application on the skin. Polymer 2014, 6, 479– 490,  DOI: 10.3390/polym6020479
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    34. 34
      Pesic, M.; Markovic, J. Z.; Jankovic, D.; Kanazir, S.; Markovic, I. D.; Rakic, L.; Ruzdijic, S. Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell Line In Vitro by anticancer drugs. J. Chemother. 2006, 18, 66– 73,  DOI: 10.1179/joc.2006.18.1.66
      [Crossref], [PubMed], [CAS], Google Scholar
      34
      Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in vitro by anticancer drugs
      Pesic, M.; Markovic, J. Z.; Jankovic, D.; Kanazir, S.; Markovic, I. D.; Rakic, L.; Ruzdijic, S.
      Journal of Chemotherapy (Firenze, Italy) (2006), 18 (1), 66-73CODEN: JCHEEU; ISSN:1120-009X. (E.S.I.F.T. srl)
      Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concns. of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was obsd. Flow cytometry anal. showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the obsd. 15-fold increase in its mRNA concn. in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjtlGmsr4%253D&md5=14ba23316984daabf3638b5d064836e2
    35. 35
      Cleator, S.; Heller, W.; Coombes, R. C. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007, 8, 235– 244,  DOI: 10.1016/S1470-2045(07)70074-8
      [Crossref], [PubMed], [CAS], Google Scholar
      35
      Triple-negative breast cancer: therapeutic options
      Cleator Susan; Heller Wolfgang; Coombes R Charles
      The Lancet. Oncology (2007), 8 (3), 235-44 ISSN:1470-2045.
      Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s7ivFKjsA%253D%253D&md5=d51518f923eb499081a8aca8f651357e
    36. 36
      Morse-Gaudio, M.; Connolly, J. M.; Rose, D. P. Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. Int. J. Oncol. 1998, 12, 1349– 1403,  DOI: 10.3892/ijo.12.6.1349
      [Crossref], [PubMed], [CAS], Google Scholar
      36
      Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype
      Morse-Gaudio, Michele; Connolly, Jeanne M.; Rose, David P.
      International Journal of Oncology (1998), 12 (6), 1349-1354CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
      Total protein kinase C (PKC) activity and the expression of 9 isoforms were detd. in the estrogen receptor (ER) pos. MCF-7 human breast cancer cell line, this line transfected to overexpress either PKC-α or erbB2, and in 3 ER neg. breast cancer cell lines. Relationships were sought between PKC and the expression of E-cadherin, α-catenin, and vimentin, and urokinase-type plasminogen activator (uPA). In general, PKC enzymic activity and the conventional isoforms PKC-α and -γ were higher in the ER neg., compared with the ER pos., cell lines. Over-expression of PKC-α by MCF-7 cells, with ER loss, was assocd. with the emergence of PKC-β expression and a relatively high level of PKC-γ, features typical of cells with increased proliferation rates; there was also a loss of PKC-ζ, consistent with acquisition of the metastatic phenotype. Transfection to overexpress erbB2, with ER retention and slowed growth, produced a decrease in PKC-α and -γ. Vimentin was expressed by the ER neg. MDA-MB-231, MDA-MB-435 and PKC-α-transfected MCF-7 cells; they also showed loss of E-cadherin and, apart from MDA-MB-435 cells, high levels of uPA secretion. The ER neg. SKBr-3 cell line was exceptional in that it had relatively low total PKC activity, low PKC-α and -γ expression and no emergence of vimentin despite loss of E-cadherin expression. Compared with the other two ER neg. cell lines, both the SKBr-3 and MDA-MB-435 cells had low PKC activity and uPA secretion. These results are consistent with the involvement of PKC, and notably the conventional isoforms, in the development of the metastatic phenotype, and specifically with the loss of E-cadherin and acquisition of vimentin expression, and the enhanced prodn. of uPA.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjs1KqtL0%253D&md5=f53205b5f96a9f0fe7440ee1726cb045
    37. 37
      Li, Z.; Wang, N.; Fang, J.; Huang, J.; Tian, F.; Li, C.; Xie, F. Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells. Oncol. Rep. 2012, 27, 1879– 1886,  DOI: 10.3892/or.2012.1728
      [Crossref], [PubMed], [CAS], Google Scholar
      37
      Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells
      Li, Zhihua; Wang, Na; Fang, Jieyu; Huang, Jintao; Tian, Fen; Li, Chaohong; Xie, Fukang
      Oncology Reports (2012), 27 (6), 1879-1886CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)
      This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-pos. human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-neg.) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric anal. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot anal. revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-pos. MCF-7 cells; while ER-neg. MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we obsd. that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFekt78%253D&md5=703cb6de8aa511f99b518e826b75d4ac
    38. 38
      Lønne, G. K.; Masoumi, K. C.; Lennartsson, J.; Larsson, C. Protein kinase Cδ supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway. J. Biol. Chem. 2009, 284, 33456– 33465,  DOI: 10.1074/jbc.M109.036186
      [Crossref], [PubMed], [CAS], Google Scholar
      38
      Protein kinase Cδ supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway
      Lonne, Gry Kalstad; Masoumi, Katarzyna Chmielarska; Lennartsson, Johan; Larsson, Christer
      Journal of Biological Chemistry (2009), 284 (48), 33456-33465CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase Cδ (PKCδ) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKCδ per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKCδ-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKCδ depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKCδ down-regulation. However, PKCδ silencing also induced increased MEK1/2 phosphorylation, indicating that PKCδ regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKCδ silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKCδ as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVCjtbzN&md5=de66a88bf9c52d033374312465f8590e
    39. 39
      Yokoyama, G.; Fujii, T.; Tayama, K.; Yamana, H.; Kuwano, M.; Shirouzu, K. PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells. Biochem. Biophys. Res. Commun. 2005, 327, 720– 726,  DOI: 10.1016/j.bbrc.2004.12.070
      [Crossref], [PubMed], [CAS], Google Scholar
      39
      PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells
      Yokoyama, Goro; Fujii, Teruhiko; Tayama, Kosuke; Yamana, Hideaki; Kuwano, Michihiko; Shirouzu, Kazuo
      Biochemical and Biophysical Research Communications (2005), 327 (3), 720-726CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)
      The effects of activating endogenous protein kinase C (PKC) on cell proliferation and the cell cycle were investigated by treating the breast cancer cell line SKBR-3 with phorbol 12-myristate 13 acetate (PMA). This inhibited cell growth in a concn.-dependent manner, causing a marked arrest of cells in G1. Pre-treatment with GF109203X completely blocked the antiproliferative effect of PMA, and pre-treatment with the PKCδ inhibitor rottlerin partially blocked it. Infecting SKBR-3 cells with an adenovirus vector contg. wild-type PKCδ, WTPKCδAdV, had similar effects on PMA. Infecting the cells with a dominant-neg. PKCδAdV construct blocked the growth inhibition induced by PMA. Downstream of PKC, PMA treatment inhibited extracellular signal-regulated kinase mitogen-activated protein kinase phosphorylation, up-regulated c-jun NH2-terminal kinase phosphorylation, and inhibited retinoblastoma (Rb) phosphorylation. These results strongly implicated PKC (mainly PKCδ) in the G1 arrest induced by PMA and suggested PKC as a target for breast cancer treatment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksFCqsQ%253D%253D&md5=d97402837c29f598bc86367b54810469
    40. 40
      Chaudhary, P. M.; Roninson, I. B. Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists. Oncol. Res. 1992, 4, 281– 290
      [PubMed], [CAS], Google Scholar
      40
      Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase C agonists
      Chaudhary, Preet M.; Roninson, Igor B.
      Oncology Research (1992), 4 (7), 281-90CODEN: ONREE8; ISSN:0965-0407.
      P-glycoprotein, encoded by the MDRI (multidrug resistance) gene, is a transmembrane efflux pump for various lipophilic compds. MDRI Is expressed in several types of normal human tissues and in a variety of tumors, where its expression has been correlated with resistance to chemotherapy. Some P-glycoprotein-overexpressing multidrug-resistant cell lines contain elevated amts. of protein kinase C (PKC). PKC activation was shown to increase the level of drug resistance in several cell lines, but the functional assocn. of PKC with P-glycoprotein-mediated multidrug resistance remains unclear. We have studied the effects of lymphocyte-activating agents on P-glycoprotein activity in normal human lymphocytes, and found that 12-O-tetradecanoylphorbol-13-acetate (TPA), an efficient agonist of PKC, increased the activity as well as the levels of P-glycoprotein in these cells. TPA also increased P-glycoprotein expression in several cell lines derived from different types of leukemias and solid tumors. The increase in MDRI gene expression was obsd. at both the protein and RNA levels. Induction of MDRI mRNA was apparent as early as two hours after the addn. of TPA. Diacylglycerol (DAG), a physiol. stimulant of PKC, also increased the expression of MDRI mRNA and P-glycoprotein. The induction of MDRI expression ty TPA and DAG was suppressed by staurosporine, a protein kinase inhibitor. The results suggest that MDRI gene expression in different cell types is regulated by a PKC-mediated pathway. This finding has implications for the emergence of multidrug resistance in vitro and in vivo.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhtFKgtrs%253D&md5=8dee316933f826f6cc70325b4daa9bec
    41. 41
      Al-Katib, A. M.; Smith, M. R.; Kamanda, W. S.; Pettit, G. R.; Hamdan, M.; Mohamed, A. N.; Chelladurai, B.; Mohammad, R. M. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res. 1998, 4, 1305– 1314
      [PubMed], [CAS], Google Scholar
      41
      Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts
      Al-Katib, Ayad M.; Smith, Mitchell R.; Kamanda, William S.; Pettit, George R.; Hamdan, Mohammed; Mohamed, Anwar N.; Chelladurai, Bhadrani; Mohammad, Ramzi M.
      Clinical Cancer Research (1998), 4 (5), 1305-1314CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor activity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (DLCL). The cell line (WSU-DLCL2) grows in liq. culture and forms s.c. tumors in mice with severe combined immune deficiency. WSU-DLCL2 is a mature B-cell line (IgGλ) that is neg. for EBV nuclear antigen, expresses the multidrug resistance phenotype, and has t(14;18)(q32;q21) plus other chromosomal aberrations. Exposure of the WSU-DLCL2 cells to Bryo1 in culture reversed the multidrug resistance phenotype within 24 h. A functional assay revealed a 4-fold increase in [3H]vincristine accumulation in Bryo1-treated cells compared with control. Vincristine (VCR), doxorubicin, Bryo1, and 1-β-D-arabinofuranosylcytosine showed no clin. significant activity when given alone to WSU-DLCL2-bearing severe combined immune deficiency mice. However, when given 24 h before each cytotoxic agent, Bryo1 substantially increased the antitumor activity of VCR but not 1-β-D-arabinofuranosylcytosine. There was a statistically significant (P < 0.001) decrease in the expression of P-glycoprotein in WSU-DLCL2 tumors taken from Bryo1-treated animals compared with untreated controls. In vivo, a competitive reverse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate that Bryo1-induced down-regulation of mdr1 might be one mechanism by which Bryo1 potentiates VCR activity. The sequential use of both agents resulted in clin. significant antitumor activity in this lymphoma model.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjt1yiu7k%253D&md5=de249ff25075e98bcfaa894bffe1aa17
    42. 42
      Fronza, M.; Murillo, R.; Ślusarczyk, S.; Adams, M.; Hamburger, M.; Heinzmann, B.; Laufer, S.; Merfort, I. In vitro cytotoxic activity of abietane diterpenes from Peltodon longipes as well as Salvia miltiorrhiza and Salvia sahendica. Bioorg. Med. Chem. 2011, 19, 4876– 4881,  DOI: 10.1016/j.bmc.2011.06.067
      [Crossref], [PubMed], [CAS], Google Scholar
      42
      In vitro cytotoxic activity of abietane diterpenes from Peltodon longipes as well as Salvia miltiorrhiza and Salvia sahendica
      Fronza, M.; Murillo, R.; Slusarczyk, S.; Adams, M.; Hamburger, M.; Heinzmann, B.; Laufer, S.; Merfort, I.
      Bioorganic & Medicinal Chemistry (2011), 19 (16), 4876-4881CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Phytochem. investigations of the n-hexane ext. from the roots of Peltodon longipes (Lamiaceae) resulted in the isolation of 12 known abietane diterpenes (1-12). Structures were established on the basis of one and two dimensional NMR spectroscopic data (1H and 13C, COSY, HSQC and HMBC), electron ionization mass spectrometric anal. (EIMS) as well as comparison with data from literature. These compds., as well as eight known diterpenes (13-19) from Salvia miltiorrhiza, and two from Salvia sahendica (20 and 21) were evaluated for their cytotoxic effects in human pancreatic (MIAPaCa-2) and melanoma (MV-3) tumor cell lines using the MTT assay. Tanshinone IIa (13), 7α-acetoxyroyleanone (1), 1,2-dihydrotanshinone (16) and cryptotanshinone (14) had the highest cytotoxic effects in MIAPaCa-2, displaying IC50 of 1.9, 4.7, 5.6, and 5.8 μM, resp. Structure-activity relationships of abietane diterpenoid quinones are discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFWhsr8%253D&md5=201441bde663628ed5abbce773b762a2
    43. 43
      Fronza, M.; Lamy, E.; Günther, S.; Heinzmann, B.; Laufer, S.; Merfort, I. Abietane diterpenes induce cytotoxic effects in human pancreatic cancer cell line MIA PaCa-2 through different modes of action. Phytochemistry 2012, 78, 107– 119,  DOI: 10.1016/j.phytochem.2012.02.015
      [Crossref], [PubMed], [CAS], Google Scholar
      43
      Abietane diterpenes induce cytotoxic effects in human pancreatic cancer cell line MIA PaCa-2 through different modes of action
      Fronza, Marcio; Lamy, Evelyn; Guenther, Stefan; Heinzmann, Berta; Laufer, Stefan; Merfort, Irmgard
      Phytochemistry (Elsevier) (2012), 78 (), 107-119CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
      Abietane diterpenes, esp. those contg. quinone moieties, are often reported to have cytotoxic effects on cancer cell lines. They deserve greater attention because several cancer chemotherapeutic agents also possess the quinone structural feature. To date, very little is known about their cytotoxic mol. modes of action. In the present study, 5 diterpenes, 7α-acetoxyroyleanone, horminone, royleanone, 7-ketoroyleanone, and sugiol which were previously isolated from the medicinal plant Peltodon longipes were shown to possess cytotoxic activity against the human pancreatic cancer cell line MIA PaCa-2. 7α-Acetoxyroyleanone, horminone, and royleanone were demonstrated to possess alkylating properties using the nucleophile 4-(4-nitrobenzyl)pyridine. However, no clear correlation between the alkylating properties and cytotoxicity of these diterpenes was obsd. Furthermore, the relaxation activity of human DNA topoisomerases I and II was found to be influenced by these compds., with 7-ketoroyleanone and sugiol being the most active. These 2 diterpenes preferentially inhibited topoisomerase I and exhibited lower IC50 values than the classical topoisomerase I inhibitor camptothecin. Mol. docking studies revealed possible interactions of diterpenes with topoisomerase I, indicating that these compds. do not form the drug-enzyme-DNA covalent ternary complex as obsd. with camptothecin. A binding pocket located at the surface of the DNA-interaction site was proposed. Moreover, the ability of the 5 diterpenes to generate DNA-strand breaks in single cells was confirmed using the alk. comet assay. As expected, these diterpenes also influenced cell cycle progression and arrested cells in different phases of the cell cycle, primarily the G1/G0 and S-phases. Interestingly, the diterpenes only exhibited a slight ability to induce apoptotic cell death and failed to generate intracellular reactive oxygen species. These results provide addnl. understanding of the cytotoxic effects of abietane diterpenes. Depending on their functional groups, we propose that abietane diterpenes utilize different mechanisms to induce cell death.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms12ntrY%253D&md5=a59ba3fd154c9ae8d8f565a2b4db1106
    44. 44
      Islam, M. T. Diterpenes and their derivatives as potential anticancer agents. Phytother. Res. 2017, 31, 691– 712,  DOI: 10.1002/ptr.5800
      [Crossref], [PubMed], [CAS], Google Scholar
      44
      Diterpenes and Their Derivatives as Potential Anticancer Agents
      Islam, Muhammad Torequl
      Phytotherapy Research (2017), 31 (5), 691-712CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
      As therapeutic tools, diterpenes and their derivs. have gained much attention of the medicinal scientists nowadays. It is due to their pledging and important biol. activities. This review congregates the anticancer diterpenes. For this, a search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chem. Society and misc. databases from Jan. 2012 to Jan. 2017 for the published articles. A total 28, 789 published articles were seen. Among them, 240 were included in this study. More than 250 important anticancer diterpenes and their derivs. were seen in the databases, acting in the different pathways. Some of them are already under clin. trials, while others are in the nonclin. and/or pre-clin. trials. In conclusion, diterpenes may be one of the lead mols. in the treatment of cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXms12nsrk%253D&md5=b8e2b667a67a0736a57ced8ea0a900b2
    45. 45
      Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3– 25,  DOI: 10.1016/S0169-409X(96)00423-1
      [Crossref], [CAS], Google Scholar
      45
      Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
      Lipinski, Christopher A.; Lombardo, Franco; Dominy, Beryl W.; Feeney, Paul J.
      Advanced Drug Delivery Reviews (1997), 23 (1-3), 3-25CODEN: ADDREP; ISSN:0169-409X. (Elsevier)
      A review with 50 refs. Exptl. and computational approaches to est. soly. and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol. wt. (MWT) is >500 and the calcd. Log P (CLogP) is >5. Computational methodol. for the rule-based Moriguchi Log P (MLogP) calcn. is described. Turbidimetric soly. measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric soly. than leads in the pre-HTS era. In the development setting, soly. calcns. focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. thermodn. soly. measurements.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktlKlsQ%253D%253D&md5=405f70b0594d428f1275e1d56642cd3a
    46. 46
      Areche, C.; Schmeda-Hirschmann, G.; Theoduloz, C.; Rodríguez, J. A. Gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean Lamiaceae Sphacele chamaedryoides (Balbis) Briq. J. Pharm. Pharmacol. 2009, 61, 1689– 1697,  DOI: 10.1211/jpp.61.12.0015
      [Crossref], [PubMed], [CAS], Google Scholar
      46
      Gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean Lamiaceae Sphacele chamaedryoides (Balbis) Briq
      Areche, Carlos; Schmeda-Hirschmann, Guillermo; Theoduloz, Cristina; Rodriguez, Jaime A.
      Journal of Pharmacy and Pharmacology (2009), 61 (12), 1689-1697CODEN: JPPMAB; ISSN:0022-3573. (Pharmaceutical Press)
      The aim of this report was to isolate, identify and assess the gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean medicinal plant Sphacele chamaedryoides (Balbis) Briq. (Lamiaceae). The isolated compds. were identified by spectroscopic means. The gastroprotective effect of the compds. was studied on the HCl/EtOH-induced gastric lesions model in mice. The cytotoxicity of the compds. was assessed on human normal lung fibroblasts (MRC-5) and gastric adenocarcinoma cells (AGS). From the aerial parts of the plant, five phenolic and five p-quinone abietanes, the sesquiterpene spathulenol and two flavonoids were obtained. The main diterpene from the plant was carnosol. Lansoprazole at 20 mg/kg reduced gastric lesions by 64.7% (P < 0.01), being statistically similar to carnosol at doses of 10 and 20 mg/kg; the percent lesion redn. with 7 at 5 mg/kg was 49.3%. At a single oral dose of 5 mg/kg, the diterpenes bearing a p-quinone moiety - 6,7-dehydroroyleanone (1), royleanone (2), 7,20-epoxyroyleanone (3), taxoquinone (5) and horminone (6) - presented a gastroprotective effect of 54.4, 70.8, 65.0, 35.8 and 52.7%, resp. Of the C-7 hydroxy derivs., the activity was much lower for the 7β-OH isomer. The phenolic diterpenes 7 and 7-oxo-11,12,14-trihydroxy-8,11,13-abietatrien-20-al (8) inhibited gastric lesions by 49.3 and 53.0%, resp. Royleanone (2), 7,20-epoxyroyleanone (3), horminone (6), 8 and spathulenol proved to be cytotoxic with IC50 values in the range of 11-67 μM. The selective cytotoxicity of compds. 1 (IC50: 61 and 366 μM) and 5 (IC50: 310 and 27 μM) against AGS cells and fibroblasts, resp., merit addnl. studies. All the abietanes obtained from S. chamaedryoides present either one or two phenolic OH groups, a quinone system, or both. Several compds. present in the plant showed higher gastroprotective effect than lansoprazole. The cytotoxic effect of most compds. was found at fairly high concns. and lacked cell specificity. Further studies are required using different tumor cell lines and viability/proliferation assays to assess the specificity of the isolated compds. The selective cytotoxicity of compds. 1 and 5 against AGS cells and fibroblasts, resp., merit addnl. studies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXitFGqs70%253D&md5=2518d9811d058161c294b36ae4e8c32f
    47. 47
      Kusumoto, N.; Aburai, N.; Ashitani, T.; Takahashi, K.; Kimura, K.-i. Pharmacological prospects of oxygenated abietane-type diterpenoids from Taxodium distichum cones. Adv. Biol. Chem. 2014, 4, 109– 115,  DOI: 10.4236/abc.2014.42015
      [Crossref], [CAS], Google Scholar
      47
      Pharmacological prospects of oxygenated abietane-type diterpenoids from Taxodium distichum cones
      Kusumoto, Norihisa; Aburai, Nobuhiro; Ashitani, Tatsuya; Takahashi, Koetsu; Kimura, Ken-ichi
      Advances in Biological Chemistry (2014), 4 (2), 109-115, 7 pp.CODEN: ABCDAS; ISSN:2162-2191. (Scientific Research Publishing, Inc.)
      Eight naturally occurring diterpenoids, including 6,7-dehydroroyleanone, taxodal, taxodione, salvinolone, 14-deoxycoleon U, 5,6-dehydrosugiol, sandaracopimaric acid, and xanthoperol were isolated from Taxodium distichum cones and their biol. properties evaluated in vitro against six different biol. screening targets. Taxodione showed potent activity against a no. of different targets, and salvinolone and 14-deoxycoleon U showed remarkable inhibitory activities against prolyl oligopeptidase (POP) and 17α-hydroxylase/C17,20-lyase (CYP17), resp. These three compds. also showed strong cytotoxic activities against HL60 and K562 human leukemia cells. The structure-activity relationships of these compds. have also been considered. The findings in this study could lead to enhanced pharmacol. prospects for the natural abietane-type diterpenoids consisting in conifer cones.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgtbjK&md5=97b3d50fbac17187f9829f35775e229b
    48. 48
      Li, S.; Wang, P.; Deng, G.; Yuan, W.; Su, Z. Cytotoxic compounds from invasive giant salvinia (Salvinia molesta) against human tumor cells. Bioorg. Med. Chem. Lett. 2013, 23, 6682– 6687,  DOI: 10.1016/j.bmcl.2013.10.040
      [Crossref], [PubMed], [CAS], Google Scholar
      48
      Cytotoxic compounds from invasive giant salvinia (Salvinia molesta) against human tumor cells
      Li, Shiyou; Wang, Ping; Deng, Guangrui; Yuan, Wei; Su, Zushang
      Bioorganic & Medicinal Chemistry Letters (2013), 23 (24), 6682-6687CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Giant salvinia (Salvinia molesta) is one of the most noxious invasive species in the world. Bioactivity-guided fractionation of ethanol ext. of giant salvinia led to the isolation of 50 compds. Of the six new compds. (1-6), salviniol (1) is a rare abietane diterpene with a new ferruginol-menthol coupled skeleton and both salviniside I (2) and salviniside II (3) are novel benzofuran glucose conjugates with unique 10-membered macrodiolide structures. Sixteen abietane diterpenes (1, 7-17, and 19-22) demonstrated in vitro activities against human tumor cells, and 7 and 8 showed selective cytotoxicity to tumor cells over normal cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCrtLbI&md5=d004b9c7624b9ee7c23f9a789a088663
    49. 49
      Jonathan, L. T.; Che, C.-T.; Pezzuto, J. M.; Fong, H. H. S.; Farnsworth, N. R. 7-O-Methylhorminone and other cytotoxic diterpene quinones from Lepechinia bullata. J. Nat. Prod. 1989, 52, 571– 575,  DOI: 10.1021/np50063a016
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      49
      7-O-methylhorminone and other cytotoxic diterpene quinones from Lepechinia bullata
      Jonathan, Lydia T.; Che, Chun Tao; Pezzuto, John M.; Fong, Harry H. S.; Farnsworth, Norman R.
      Journal of Natural Products (1989), 52 (3), 571-5CODEN: JNPRDF; ISSN:0163-3864.
      Three cytotoxic diterpene quinones, 6,7-dehydroroyleanone, horminone, and 7-O-methylhorminone, were isolated from an MeOH ext. of L. bullata after bioassay-directed fractionation and identified by 1H and 13C NMR, UV, IR, and mass spectroscopy and by comparison with authentic samples. 7-O-Methylhorminone is a new natural product.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltFags7w%253D&md5=9265cf793c3d78ab7382593bf93d8185
    50. 50
      Fernandes, A. S.; Serejo, J.; Gaspar, J.; Cabral, F.; Bettencourt, A. F.; Rueff, J.; Castro, M.; Costa, J.; Oliveira, N. G. Oxidative injury in V79 Chinese hamster cells: protective role of the superoxide dismutase mimetic MnTM-4-PyP. Cell Biol. Toxicol. 2010, 26, 91– 101,  DOI: 10.1007/s10565-009-9120-3
      [Crossref], [PubMed], [CAS], Google Scholar
      50
      Oxidative injury in V79 Chinese hamster cells: protective role of the superoxide dismutase mimetic MnTM-4-PyP
      Fernandes, Ana S.; Serejo, Joao; Gaspar, Jorge; Cabral, Fatima; Bettencourt, Ana F.; Rueff, Jose; Castro, Matilde; Costa, Judite; Oliveira, Nuno G.
      Cell Biology and Toxicology (2010), 26 (2), 91-101CODEN: CBTOE2; ISSN:0742-2091. (Springer)
      Oxidative cell injury could be induced by different reactive oxygen species (ROS) operating in multiple pathways. The present work is focused on three different models of oxidative stress: the xanthine/xanthine oxidase system (XXO), an extracellular superoxide anion generator; tert-butylhydroperoxide (TBHP), an analog of lipid hydroperoxides; and doxorubicin (Dox), an anticancer drug. Superoxide and peroxyl radicals, among other ROS, could be effectively scavenged by MnTM-4-PyP, a polyfunctional catalytic antioxidant. In this report, we have addressed the role of MnTM-4-PyP on the protection against the cytotoxicity induced by the three aforementioned oxidants. The effect of MnTM-4-PyP (0.1-100 μM) was evaluated in V79 fibroblasts using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide redn. and the crystal violet assays, as well as the mitotic index. Also, the generation of intracellular ROS was studied by the fluorescent probe dihydroethidium. MnTM-4-PyP has shown significant protective effects against the cytotoxicity of XXO and TBHP, increasing the cell viability in approx. 40% and reducing the intracellular level of ROS. However, no considerable protection occurred against Dox. The three oxidants caused a mitotic index redn. that was not altered by MnTM-4-PyP. In summary, MnTM-4-PyP appears to be a promising agent for the protection against oxidative injury. However, it has shown differential responses, reinforcing the need to study different exptl. models for the adequate evaluation of its potentialities as a catalytic antioxidant.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXis1eht78%253D&md5=0136924d1d14c68be73bbcb579591730
    51. 51
      Guerreiro, P. S.; Fernandes, A. S.; Costa, J. G.; Castro, M.; Miranda, J. P.; Oliveira, N. G. Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells. Mutat. Res. 2013, 757, 140– 147,  DOI: 10.1016/j.mrgentox.2013.08.003
      [Crossref], [PubMed], [CAS], Google Scholar
      51
      Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells
      Guerreiro, Patricia S.; Fernandes, Ana Sofia; Costa, Joao G.; Castro, Matilde; Miranda, Joana P.; Oliveira, Nuno G.
      Mutation Research, Genetic Toxicology and Environmental Mutagenesis (2013), 757 (2), 140-147CODEN: MRGMFI; ISSN:1383-5718. (Elsevier B.V.)
      Pharmacol. inhibition of DNA repair is a promising approach to increase the effectiveness of anticancer drugs. The chemotherapeutic drug doxorubicin (Dox) may act, in part, by causing oxidative DNA damage. The base excision repair (BER) pathway effects the repair of many DNA lesions induced by reactive oxygen species (ROS). Methoxyamine (MX) is an indirect inhibitor of apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional BER protein. We have evaluated the effects of MX on the cytotoxicity and genotoxicity of Dox in MDA-MB-231 metastatic breast cancer cells. MX has little effects on the viability and proliferation of Dox-treated cells. However, as assessed by the cytokinesis-block micronucleus assay (CBMN), MX caused a significant 1.4-fold increase (P < 0.05) in the frequency of micronucleated binucleated cells induced by Dox, and also altered the distribution of the nos. of micronuclei. The fluorescence probe dihydroethidium (DHE) indicated little prodn. of ROS by Dox. Overall, our results suggest differential outcomes for the inhibition of APE1 activity in breast cancer cells exposed to Dox, with a sensitizing effect obsd. for genotoxicity but not for cytotoxicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVOntrbJ&md5=ded80757ad199b27434232adbe737f66
    52. 52
      Pereira, P.; Bernardo-Gil, M. G.; Cebola, M. J.; Mauricio, E.; Romano, A. Supercritical fluid extracts with antioxidant and antimicrobial activities from myrtle (Myrtus communis L.) leaves. Response surface optimization. J. Supercrit. Fluids 2013, 83, 57– 64,  DOI: 10.1016/j.supflu.2013.08.010
      [Crossref], [CAS], Google Scholar
      52
      Supercritical fluid extracts with antioxidant and antimicrobial activities from myrtle (Myrtus communis L.) leaves. Response surface optimization
      Pereira, Paula; Bernardo-Gil, M. Gabriela; Cebola, M. Joao; Mauricio, Elisabete; Romano, Anabela
      Journal of Supercritical Fluids (2013), 83 (), 57-64CODEN: JSFLEH; ISSN:0896-8446. (Elsevier B.V.)
      Supercrit. Fluid Extn. (SFE) was used to obtain myrtle leaf exts., and to study the antioxidant capacity (AOC) and in vitro antimicrobial activity of those exts. To optimize the SFE operational conditions, the response surface methodol. (RSM) was adopted. The parameters studied were: pressure (P), within the range 10 to 30 MPa; temp. (T), between 35 and 60 and supercrit. carbon dioxide (SCCO2) flow rate (Q) within the range 0.15 to 0.45 kg h-1. The results show a good fit to the proposed model and the optimal conditions obtained (23 MPa, 45, and SCCO2 flow rate of 0.3 kg h-1) were within the exptl. range. The predicted values agreed with exptl. ones, thus indicating the suitability of the RSM model for the optimization of the extn. conditions being investigated. With those values remaining const., ethanol as a co-solvent was then studied. There was an obsd. rise in AOC as the amt. of ethanol increased, within the range studied (0-30% ethanol). The ext. with the highest AOC was tested for its antimicrobial activity against gram-pos. and gram-neg. bacteria. The min. inhibitory concn. (MIC) values obtained showed significant inhibitory effect against gram-pos. bacteria.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yitLbM&md5=5b048d3faf72f168b9dc3afaa9620186
    53. 53
      ICH Harmonised Tripartite Guideline Q2(R1). Validation of Analytical Procedures: Text and Methodology. In International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; European Medicines Agency: Chicago, IL, 2005.
      Google Scholar
      There is no corresponding record for this reference.
    54. 54
      Leão, M.; Soares, J.; Gomes, S.; Raimundo, L.; Ramos, H.; Bessa, C.; Queiroz, G.; Domingos, S.; Pinto, M.; Inga, A.; Cidade, H.; Saraiva, L. Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction. Life Sci. 2015, 142, 60– 65,  DOI: 10.1016/j.lfs.2015.10.015
      [Crossref], [PubMed], [CAS], Google Scholar
      54
      Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
      Leao, Mariana; Soares, Joana; Gomes, Sara; Raimundo, Liliana; Ramos, Helena; Bessa, Claudia; Queiroz, Gloria; Domingos, Sofia; Pinto, Madalena; Inga, Alberto; Cidade, Honorina; Saraiva, Lucilia
      Life Sciences (2015), 142 (), 60-65CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
      Chalcones are naturally occurring compds. with recognized anticancer activity. It was recently shown that the O-prenyl deriv. (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumor cells compared to its precursor. With this study, we aimed to investigate the mol. mechanism underlying the improved tumor cytotoxicity of prenylchalcone 2. The impact of chalcones 1 and 2 on p53-MDM2 interaction was investigated using yeast growth-inhibitory and p53 transactivation assays. Their tumor growth-inhibitory effects were assessed on human colon adenocarcinoma HCT116 cell lines with wild-type p53 and its p53-null deriv., followed by anal. of cell cycle and apoptosis. In tumor cells, the activation of a mitochondrial pathway was checked by anal. of reactive oxygen species generation, Bax mitochondrial translocation and cytochrome c release. Addnl., the up-regulation of p53 transcriptional activity was investigated through Western blot anal. of p53 target expression levels, and the disruption of the p53-MDM2 interaction was confirmed by co-immunopptn. The potent cell tumor growth-inhibitory activity of prenylchalcone 2 was assocd. with the activation of a p53 pathway involving cell cycle arrest and a mitochondria-dependent apoptosis. Furthermore, a correlation between the distinct cytotoxicity of chalcones 1 and 2 and their ability to disrupt the p53-MDM2 interaction was established. This work shows that prenylation is a determinant factor for the enhancement of chalcones tumor cytotoxicity by improving their ability to disrupt the p53-MDM2 interaction. Prenylchalcone 2 represents a starting basis for the design of new p53-MDM2 interaction inhibitors with improved antitumor properties.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslSjsbbM&md5=0a41db8b36c977761c6d98b31f0aecfc
    55. 55
      Soares, J.; Pereira, N. A. L.; Monteiro, Â.; Leão, M.; Bessa, C.; dos Santos, D. J. V. A.; Raimundo, L.; Queiroz, G.; Bisio, A.; Inga, A.; Pereira, C.; Santos, M. M. M.; Saraiva, L. Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction. Eur. J. Pharm. Sci. 2015, 66, 138– 147,  DOI: 10.1016/j.ejps.2014.10.006
      [Crossref], [PubMed], [CAS], Google Scholar
      55
      Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction
      Soares, Joana; Pereira, Nuno A. L.; Monteiro, Angelo; Leao, Mariana; Bessa, Claudia; dos Santos, Daniel J. V. A.; Raimundo, Liliana; Queiroz, Gloria; Bisio, Alessandra; Inga, Alberto; Pereira, Clara; Santos, Maria M. M.; Saraiva, Lucilia
      European Journal of Pharmaceutical Sciences (2015), 66 (), 138-147CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
      One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous neg. regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams and the evaluation of their biol. effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compds. 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The mol. mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53+/+) and in its isogenic deriv. without p53 (HCT116 p53-/-). Indeed, using these cells, we demonstrated that oxazoloisoindolinone 3a exhibited a p53-dependent in vitro antitumor activity through induction of G0/G1-phase cell cycle arrest and apoptosis. The selective activation of a p53-apoptotic pathway by oxazoloisoindolinone 3a was further supported by the occurrence of PARP cleavage only in p53-expressing HCT116 cells. Moreover, oxazoloisoindolinone 3a led to p53 protein stabilization and to the up-regulation of p53 transcriptional activity with increased expression levels of several p53 target genes, as p21(WAF1/CIP1), MDM2, BAX and PUMA, in p53+/+ but not in p53-/- HCT116 cells. Addnl., the ability of oxazoloisoindolinone 3a to block the p53-MDM2 interaction in HCT116 p53+/+ cells was confirmed by co-immunopptn. Finally, the mol. docking anal. of the interactions between the synthesized compds. and MDM2 revealed that oxazoloisoindolinone 3a binds to MDM2. Altogether, this work adds, for the first time, the oxazoloisoindolinone scaffold to the list of chemotypes activators of a wild-type p53-pathway with promising antitumor activity. Moreover, it may open the way to the development of a new class of p53-MDM2 interaction inhibitors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslKjtrrP&md5=5bb41ff3e1afbd46b39f8f48569c2dbc
    56. 56
      Fischedick, J. T.; Pesic, M.; Podolski-Renic, A.; Bankovic, J.; de Vos, R. C. H.; Perić, M.; Todorović, S.; Tanic, N. Cytotoxic activity of sesquiterpene lactones from Inula britannica on human cancer cell lines. Phytochem. Lett. 2013, 6, 246– 252,  DOI: 10.1016/j.phytol.2013.02.006
      [Crossref], [CAS], Google Scholar
      56
      Cytotoxic activity of sesquiterpene lactones from Inula britannica on human cancer cell lines
      Fischedick, Justin T.; Pesic, Milica; Podolski-Renic, Ana; Bankovic, Jasna; de Vos, Ric C. H.; Peric, Marija; Todorovic, Sladjana; Tanic, Nikola
      Phytochemistry Letters (2013), 6 (2), 246-252CODEN: PLHEBK; ISSN:1874-3900. (Elsevier B.V.)
      Five new sesquiterpene lactones (1-5) were isolated from Inula britannica collected in the wild from Serbia along with five known compds. (6-10). Sesquiterpene lactones were isolated using centrifugal partition chromatog. followed by combination of flash chromatog. and semi-preparative HPLC. Isolated compds. were screened for cytotoxic activity on four different human cancer cell lines and their multi-drug resistant counterparts, as well as on normal human keratinocytes. Sesquiterpene lactones showed similar cytotoxic activity toward drug sensitive and drug resistant cancer cell lines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntV2hsbk%253D&md5=15f881de1d9d40babe98af6ec26ad12f

  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00512.

    • 1H NMR and 13C NMR spectra of compound (3), HPLC-DAD analytical profile of plant extracts and UV-spectra overlay, and analytical parameters for HPLC-DAD quantification method (PDF)

    Terms & Conditions

    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

PDF [ 913KB]

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

OOPS

You have to login with your ACS ID befor you can login with your Mendeley account.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect

This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.

CONTINUE