Glibenclamide induces apoptosis through inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels and intracellular Ca2+ release in HepG2 human hepatoblastoma cells

Glibenclamide, an inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels, induced apoptosis in a dose- and time-dependent manner in HepG2 human hepatoblastoma cells. Glibenclamide increased intracellular Ca2+ concentration, which was significantly inhibited by Ca2+ release blockers dantrolene and TMB-8. BAPTA/AM, an intracellular Ca2+ chelator, and the Ca2+ release blockers significantly inhibited glibenclamide-induced apoptosis. Glibanclamide also increased intracellular Cl- concentration, which was significantly blocked by CFTR Cl- channel activators levamisole and bromotetramisole. These activators also significantly inhibited both intracellular Ca2+ release and apoptosis induced by glibenclamide. The expression of CFTR protein in the cells was confirmed by Western blot analysis. These results suggest that glibenclamide induced apoptosis through inhibition of CFTR Cl- channels and intracellular Ca2+ release and that this protein may be a good target for treatment of human hepatomas. (C) 1999 Academic Press.