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Roles of Volume-sensitive Cl− Channel in Cisplatin-induced Apoptosis in Human Epidermoid Cancer Cells

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Abstract

The anti-cancer drug cisplatin induces apoptosis by damaging DNA. Since a stilbene-derivative blocker of Cl−/HCO −3 exchangers and Cl− channels, SITS, is known to induce cisplatin resistance in a manner independent of intracellular pH and extracellular HCO −3 , we investigated the relation between cisplatin-induced apoptosis and Cl− channel activity in human adenocarcinoma KB cells. A stilbene derivative, DIDS, reduced cisplatin-induced caspase-3 activation and cell death, which were detected over 18 h after treatment with cisplatin. DIDS was also found to reduce sensitivity of KB cells to 5-day exposure to cisplatin. Whole-cell patch-clamp recordings showed that KB cells functionally express volume-sensitive outwardly rectifying (VSOR) Cl− channels which are activated by osmotic cell swelling and sensitive to DIDS. Pretreatment of the cells with cisplatin for 12 h augmented the magnitude of VSOR Cl− current. Thus, it is concluded that cisplatin-induced cytotoxicity in KB cells is associated with augmented activity of a DIDS-sensitive VSOR Cl− channel and that blockade of this channel is, at least in part, responsible for cisplatin resistance induced by a stilbene derivative.

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Acknowledgments

The authors are grateful to E. Maeno, H. Liu and T. Numata for discussion, M. Ohara, S. Tanaka and K. Shigemoto for technical assistance, and T. Okayasu for secretarial assistance. This work was supported by a Grant-in-Aid for Scientific Research from MEXT of Japan.

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Authors and Affiliations

  1. Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan

    T. Shimizu, E.L. Lee, H. Inoue & Y. Okada

  2. Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, 807-8555, Japan

    T. Ise & K. Kohno

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  1. T. Ise
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  2. T. Shimizu
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  3. E.L. Lee
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  4. H. Inoue
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  5. K. Kohno
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  6. Y. Okada
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Correspondence to Y. Okada.

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Ise, T., Shimizu, T., Lee, E. et al. Roles of Volume-sensitive Cl− Channel in Cisplatin-induced Apoptosis in Human Epidermoid Cancer Cells. J Membrane Biol 205, 139–145 (2005). https://doi.org/10.1007/s00232-005-0779-y

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  • DOI: https://doi.org/10.1007/s00232-005-0779-y

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