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KMID : 0617220030140010239
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Duksung Bulletin Phamaceutical Sciences
2003 Volume.14 No. 1 p.239 ~ p.245
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Role of Ca^(2+)-activated Cl^(-) channels in the mechanism of apoptosis induced by cyclosporin A in a human hepatoma cell line
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Kim, Jung-Ae
Kang, Young Shin/Lee, Yong Soo
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Abstract
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The mechanism of apoptosis induced by cyclosporin A (CsA) in a human hepatoma cell line was investigated. CsA induced apoptosis in a dose and time-dependent manner in HepG2 human hepatoma cells. CsA induced Cl^(-) efflux, which was significantly blocked by niflumic acid (NA), a specific inhibitor, and flufenamic acid (FA), 5-nitro-2-(3-phenyl-propylamino)-benzoate (NPPB), and 4.4´-disothiocyanoto-stibene-2,2´-disulfonic acid (DIDS), non-specific inhibitors of Ca^(+2)-activated Cl^(-) channels (CaCCs), not by calyculin A, an inhibitor of K^(+), Cl^(-)-cotransport. In addition, CsA did not alter intracellular K^(+) concentration. Moreover, CsA increased intracellular Ca^(+2) concentration, and treatment with BAPTA/AM, an intracellular Ca^(+2) chelator, significantly inhibited the CsA-induced Cl^(-) efflux, indicating that CsA induced Cl^(-) efflux through the activation of CaCCs. Treatment with these CaCC inhibitors (NA, FA, NPPB, and DIDS) markedly prevented the CsA-induced apoptosis. Taken together, these results suggest that CaCCs may mediate apoptosis induced by CsA in HepG2 cells. Furthermore, these results provide a new insight into the novel function of CaCCs in the regulation of cancer cell apoptosis associated with perturbation of intracellular Ca^(+2) signal.
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