RT Journal Article SR Electronic T1 The Ca2+ Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 210 OP 219 DO 10.1124/mol.62.2.210 VO 62 IS 2 A1 Gabriel E. Bertolesi A1 Chanjuan Shi A1 Lindsy Elbaum A1 Christine Jollimore A1 Gabriela Rozenberg A1 Steven Barnes A1 Melanie E. M. Kelly YR 2002 UL http://molpharm.aspetjournals.org/content/62/2/210.abstract AB We show that mitogenic cells expressing T-type Ca2+channels (T-channels) are more sensitive to the antiproliferative effects of the drugs pimozide and mibefradil than cells without significant T-channel expression. The growth of Y79 and WERI-Rb1 retinoblastoma cells, as well as MCF7 breast cancer epithelial cells, all of which express T-channel current and mRNA for T-channel subunits, is inhibited by pimozide and mibefradil with IC50 values between 0.6 and 1.5 μM. Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC50 = 8 and 5 μM for pimozide and mibefradil, respectively). Neither drug seems to alter cell cycle or the expression of cyclins. Although this strong correlation between T-channel expression and growth inhibition exists, the following results suggest that the drugs inhibit cell growth via different cytotoxic pathways: 1) pimozide and mibefradil have additive effects on T-channel current inhibition, whereas the antiproliferative activity of the drugs together is synergistic; 2) an increase in the number of apoptotic Y79 and MCF7 cells and a decrease in the mRNA for the antiapoptotic geneBcl-2 is detected only in pimozide-treated cells, whereas in mibefradil-treated cells, the toxicity is primarily necrotic; and 3) growth inhibition by mibefradil is reduced in Y79 cells transfected with T-channel antisense and in differentiated Y79 cells (which have decreased T-channel expression), but growth inhibition by pimozide is affected to a lesser extent. These results suggest that pimozide and mibefradil inhibit cell proliferation via different cytotoxic pathways and that in the case of pimozide, it is unlikely that this effect is mediated solely by T-channel inhibition.