title: Impaired activity of volume-sensitive Cl- channel is involved in cisplatin resistance of cancer cells.
abstract: The platinum-based drug cisplatin is a widely used anticancer drug which acts by causing the induction of apoptosis. However, resistance to the drug is a major problem. In this study we show that the KCP-4 human epidermoid cancer cell line, which serves as a model of acquired resistance to cisplatin, has virtually no volume-sensitive, outwardly rectifying (VSOR) chloride channel activity. The VSOR chloride channel's molecular identity has not yet been determined, and semi-quantitative RT-PCR experiments in this study suggested that the channel corresponds to none of three candidate genes. However, because it is known that the channel current plays an essential role in apoptosis, we hypothesized that lack of the current contributes to cisplatin resistance in these cells and that its restoration would reduce resistance. To test this hypothesis, we attempted to restore VSOR chloride current in KCP-4 cells. It was found that treatment with trichostatin A (TSA), a histone deacetylase inhibitor, caused VSOR chloride channel function to be partially restored. Treatment of the cells with both TSA and cisplatin resulted in an increase in caspase-3 activity at 24 h and a decrease in cell viability at 48 h. These effects were blocked by simultaneous treatment of the cells with a VSOR chloride channel blocker. These results indicate that restoration of the channel's functional expression by TSA treatment leads to a decrease in the cisplatin resistance of KCP-4 cells. We thus conclude that impaired activity of the VSOR chloride channel is involved in the cisplatin resistance of KCP-4 cancer cells.
authors.affiliation: Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki, Japan.
authors.forename: Elbert L
authors.initials: EL
authors.lastname: Lee
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ise
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Numata
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Okada
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D048429:Cell Size; D002470:Cell Survival / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D010641:Phenotype; D010693:Phloretin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D053148:Caspase 3; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002945:Cisplatin; D010693:Phloretin