ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Mediating K+/H+ Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule

  • Fang-Fang Shen
    Fang-Fang Shen
    Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
  • Sheng-Yao Dai
    Sheng-Yao Dai
    Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
  • Nai-Kei Wong
    Nai-Kei Wong
    Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
    Department of Infectious Diseases, Shenzhen Third People’s Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen 518112, China
    More by Nai-Kei Wong
  • Shan Deng
    Shan Deng
    Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
    School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China
    More by Shan Deng
  • Alice Sze-Tsai Wong
    Alice Sze-Tsai Wong
    School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China
  • , and 
  • Dan Yang*
    Dan Yang
    Morningside Laboratory for Chemical Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
    *[email protected]
    More by Dan Yang
Cite this: J. Am. Chem. Soc. 2020, 142, 24, 10769–10779
Publication Date (Web):May 22, 2020
https://doi.org/10.1021/jacs.0c02134
Copyright © 2020 American Chemical Society

    Article Views

    4820

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (1)»

    Abstract

    Abstract Image

    Molecules that are capable of disrupting cellular ion homeostasis offer unique opportunities to treat cancer. However, previously reported synthetic ion transporters showed limited value, as promiscuous ionic disruption caused toxicity to both healthy cells and cancer cells indiscriminately. Here we report a simple yet efficient synthetic K+ transporter that takes advantage of the endogenous subcellular pH gradient and membrane potential to site-selectively mediate K+/H+ transport on the mitochondrial and lysosomal membranes in living cells. Consequent mitochondrial and lysosomal damages enhanced cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) via apoptosis induction and autophagy suppression with remarkable selectivity (up to 47-fold). The eradication of CSCs blunted tumor formation in mice. We believe this strategy can be exploited in the structural design and applications of next-generation synthetic cation transporters for the treatment of cancer and other diseases related to dysfunctional K+ channels.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.0c02134.

    • Details regarding the synthesis of 16, ion transport assays and mechanism studies, and biological studies (PDF)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 32 publications.

    1. Toby G. Johnson, Matthew J. Langton. Molecular Machines For The Control Of Transmembrane Transport. Journal of the American Chemical Society 2023, 145 (50) , 27167-27184. https://doi.org/10.1021/jacs.3c08877
    2. Minsu Park, Kyoung Sunwoo, Yoon-Jae Kim, Miae Won, Yunjie Xu, Jaewon Kim, Zhongji Pu, Mingle Li, Ji Young Kim, Jae Hong Seo, Jong Seung Kim. Cutting Off H+ Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells. Journal of the American Chemical Society 2023, 145 (8) , 4647-4658. https://doi.org/10.1021/jacs.2c12587
    3. Yaqian He, Mengxue Yang, Tao Wang, Liuyang Xu, Zhenhe Ma, Jian Mu, Desong Wang, Dawei Gao. Regulation of Interstitial Fluid Pressure for Improved Intratumor Drug Permeability and Nanozyme-Enhanced Chemocatalytic Therapy. ACS Sustainable Chemistry & Engineering 2022, 10 (27) , 8908-8918. https://doi.org/10.1021/acssuschemeng.2c02129
    4. Chien-Tien Chen, Jih-Sen Ho, Shu-Chih Weng. Metal-Ion Specific Recognition with Amplified Transcription from Subnanometer to Submillimeter or Real-Time Domain by Self-Assembled Vanadyl Quartets. Inorganic Chemistry 2022, 61 (14) , 5595-5606. https://doi.org/10.1021/acs.inorgchem.2c00231
    5. Hao Zhang, Ruijuan Ye, Yuguang Mu, Tianhu Li, Huaqiang Zeng. Small Molecule-Based Highly Active and Selective K+ Transporters with Potent Anticancer Activities. Nano Letters 2021, 21 (3) , 1384-1391. https://doi.org/10.1021/acs.nanolett.0c04134
    6. Qingxia Huang, Hang Su, Bin Qi, Ying Wang, Kaili Yan, Xinglin Wang, Xiangyan Li, Daqing Zhao. A SIRT1 Activator, Ginsenoside Rc, Promotes Energy Metabolism in Cardiomyocytes and Neurons. Journal of the American Chemical Society 2021, 143 (3) , 1416-1427. https://doi.org/10.1021/jacs.0c10836
    7. Prashant S. Kharkar. Cancer Stem Cell (CSC) Inhibitors in Oncology—A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives. Journal of Medicinal Chemistry 2020, 63 (24) , 15279-15307. https://doi.org/10.1021/acs.jmedchem.0c01336
    8. Shasha Lv, Xiyu Li, Li Yang, Xijun Wang, Jinxiao Zhang, Guozhen Zhang, Jun Jiang. Azopyrazole-Based Photoswitchable Anion Receptor for Dihydrogen Phosphate Transport. The Journal of Physical Chemistry A 2020, 124 (47) , 9692-9697. https://doi.org/10.1021/acs.jpca.0c08108
    9. Yue-Yang Liu, Xiao-Yong Yu, Yu-Chen Pan, Hang Yin, Shuang Chao, Yujie Li, He Ma, Minzan Zuo, Kun-Xu Teng, Jun-Li Hou, Yong Chen, Dong-Sheng Guo, Ruibing Wang, Yuxin Pei, Zhichao Pei, Jiang-Fei Xu, Xiao-Yu Hu, Chunju Li, Qing-Zheng Yang, Leyong Wang, Yu Liu, Zhan-Ting Li. Supramolecular systems for bioapplications: recent research progress in China. Science China Chemistry 2024, 67 (5) , 1397-1441. https://doi.org/10.1007/s11426-024-1971-4
    10. Yaqi Wu, Cong Li, Yanliang Wu, Jiayun Xu, Zhigang Ni, Ofer Reany, Tengfei Yan, Dingcheng Zhu, Junqiu Liu. A Reversible Light‐Driven Biomimetic K + /Na + ‐Exchanger Controls Cancer Cell Apoptosis. Advanced Functional Materials 2024, 2 https://doi.org/10.1002/adfm.202400432
    11. Xiyu Yuan, Jie Shen, Huaqiang Zeng. Artificial transmembrane potassium transporters: designs, functions, mechanisms and applications. Chemical Communications 2024, 60 (5) , 482-500. https://doi.org/10.1039/D3CC04488B
    12. Xia Qin, Jianmin Xiao, Huimin Li, Hai Huang, Hongyuan Jin, Yu Zhang, Geng Tian, Gang Wang, Guilong Zhang. Copper-based inorganic nanozymes enhance the electrical conductivity of tumors to synergistically induce the pyroptosis, ferroptosis, and apoptosis of tumors. Inorganic Chemistry Frontiers 2023, 10 (24) , 7176-7186. https://doi.org/10.1039/D3QI01748F
    13. Xiaoni Wang, Xiyang Ge, Xiaowen Guan, Jin Ouyang, Na Na. Synergistically remodulating H + /Ca 2+ gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy. Chemical Science 2023, 14 (41) , 11532-11545. https://doi.org/10.1039/D3SC03493C
    14. Narendra Kumar, Nandita Madhavan. Small molecule-derived pH-gated ion transporters. Organic & Biomolecular Chemistry 2023, 21 (29) , 5892-5905. https://doi.org/10.1039/D3OB00496A
    15. Umatai A. Hale, Nandita Madhavan. Hydrophobic cyclic dipeptides as M + /Cl − carriers. Chemical Communications 2023, 59 (46) , 7068-7071. https://doi.org/10.1039/D3CC02132G
    16. Lei He, Tianlong Zhang, Canhong Zhu, Tengfei Yan, Junqiu Liu. Crown Ether‐Based Ion Transporters in Bilayer Membranes. Chemistry – A European Journal 2023, 29 (25) https://doi.org/10.1002/chem.202300044
    17. Pengyang Xin, Linqi Xu, Wenpei Dong, Linlin Mao, Jingjing Guo, Jingjing Bi, Shouwei Zhang, Yan Pei, Chang‐Po Chen. Synthetic K + Channels Constructed by Rebuilding the Core Modules of Natural K + Channels in an Artificial System. Angewandte Chemie 2023, 135 (8) https://doi.org/10.1002/ange.202217859
    18. Pengyang Xin, Linqi Xu, Wenpei Dong, Linlin Mao, Jingjing Guo, Jingjing Bi, Shouwei Zhang, Yan Pei, Chang‐Po Chen. Synthetic K + Channels Constructed by Rebuilding the Core Modules of Natural K + Channels in an Artificial System. Angewandte Chemie International Edition 2023, 62 (8) https://doi.org/10.1002/anie.202217859
    19. Tengfei Yan, Xin Zheng, Shengda Liu, Yingping Zou, Junqiu Liu. Ion transporters: emerging agents for anticancer therapy. Science China Chemistry 2022, 65 (7) , 1265-1278. https://doi.org/10.1007/s11426-022-1258-4
    20. Huiting Yang, Jinhao Yi, Shihao Pang, Kai Ye, Zhicheng Ye, Qi Duan, Zexin Yan, Cheng Lian, Yi Yang, Linyong Zhu, Da‐Hui Qu, Chunyan Bao. A Light‐Driven Molecular Machine Controls K + Channel Transport and Induces Cancer Cell Apoptosis. Angewandte Chemie 2022, 134 (26) https://doi.org/10.1002/ange.202204605
    21. Huiting Yang, Jinhao Yi, Shihao Pang, Kai Ye, Zhicheng Ye, Qi Duan, Zexin Yan, Cheng Lian, Yi Yang, Linyong Zhu, Da‐Hui Qu, Chunyan Bao. A Light‐Driven Molecular Machine Controls K + Channel Transport and Induces Cancer Cell Apoptosis. Angewandte Chemie International Edition 2022, 61 (26) https://doi.org/10.1002/anie.202204605
    22. Giacomo Picci, Silvia Marchesan, Claudia Caltagirone. Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry. Biomedicines 2022, 10 (4) , 885. https://doi.org/10.3390/biomedicines10040885
    23. Bo Li, Jun Wu, Lei Tang, Xu Lian, Zhongwen Li, Wenfang Duan, Tong Qin, Xintong Zhao, Yuhua Hu, Chi Zhang, Tianlei Li, Jie Hao, Wenxuan Zhang, Jihong Zhang, Song Wu. Synthesis and anti-tumor activity evaluation of salinomycin C20- O -alkyl/benzyl oxime derivatives. Organic & Biomolecular Chemistry 2022, 20 (4) , 870-876. https://doi.org/10.1039/D1OB02292J
    24. Jie Yang, Guocan Yu, Jonathan L. Sessler, Injae Shin, Philip A. Gale, Feihe Huang. Artificial transmembrane ion transporters as potential therapeutics. Chem 2021, 7 (12) , 3256-3291. https://doi.org/10.1016/j.chempr.2021.10.028
    25. Arundhati Roy, Pinaki Talukdar. Recent Advances in Bioactive Artificial Ionophores. ChemBioChem 2021, 22 (20) , 2925-2940. https://doi.org/10.1002/cbic.202100112
    26. Laura E. Bickerton, Toby G. Johnson, Aidan Kerckhoffs, Matthew J. Langton. Supramolecular chemistry in lipid bilayer membranes. Chemical Science 2021, 12 (34) , 11252-11274. https://doi.org/10.1039/D1SC03545B
    27. Jie Shen, Ruijuan Ye, Huaqiang Zeng. Crystal Packing‐Guided Construction of Hetero‐Oligomeric Peptidic Ensembles as Synthetic 3‐in‐1 Transporters. Angewandte Chemie 2021, 133 (23) , 13034-13040. https://doi.org/10.1002/ange.202101489
    28. Jie Shen, Ruijuan Ye, Huaqiang Zeng. Crystal Packing‐Guided Construction of Hetero‐Oligomeric Peptidic Ensembles as Synthetic 3‐in‐1 Transporters. Angewandte Chemie International Edition 2021, 60 (23) , 12924-12930. https://doi.org/10.1002/anie.202101489
    29. Robert Pomorski, María García-Valverde, Roberto Quesada, Michał J. Chmielewski. Transmembrane anion transport promoted by thioamides. RSC Advances 2021, 11 (20) , 12249-12253. https://doi.org/10.1039/D1RA01646F
    30. Wei-Wei Haoyang, Qi Xiao, Zhongju Ye, Yonghong Fu, Dan-Wei Zhang, Jian Li, Lehui Xiao, Zhan-Ting Li, Jun-Li Hou. Gramicidin A-based unimolecular channel: cancer cell-targeting behavior and ion transport-induced apoptosis. Chemical Communications 2021, 57 (9) , 1097-1100. https://doi.org/10.1039/D0CC08073J
    31. Katrin Ganser, Lukas Klumpp, Helmut Bischof, Robert Lukowski, Franziska Eckert, Stephan M. Huber. Potassium Channels in Cancer. 2021, 253-275. https://doi.org/10.1007/164_2021_465
    32. Siddharth Adityan, Michelle Tran, Chintan Bhavsar, Sherry Y. Wu. Nano-therapeutics for modulating the tumour microenvironment: Design, development, and clinical translation. Journal of Controlled Release 2020, 327 , 512-532. https://doi.org/10.1016/j.jconrel.2020.08.016

    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.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect