The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms.
We show that mitogenic cells expressing T-type Ca(2+) 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 IC(50) values between 0.6 and 1.5 microM. Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC(50) = 8 and 5 microM 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 gene Bcl-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.
Bertolesi
Gabriel E
GE
Laboratory of Retina and Optic Nerve Research, Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.
Shi
Chanjuan
C
Elbaum
Lindsy
L
Jollimore
Christine
C
Rozenberg
Gabriela
G
Barnes
Steven
S
Kelly
Melanie E M
ME
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D020748:Mibefradil / Q000494:pharmacology*; D010868:Pimozide / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010868:Pimozide; D020748:Mibefradil