Action of calcium antagonists on multidrug resistant cells. Specific cytotoxicity independent of increased cancer drug accumulation.

Previous studies have shown that calcium channel blockers can overcome, at least partially, multidrug resistance (MDR). This study was undertaken to attempt to determine the mechanisms whereby these agents bring about this effect. Their influence on the uptake and retention of several cancer drugs and on the toxic actions of these compounds was assessed employing MDR cell lines from several species. The wild-type drug sensitive parent cells proved to be more susceptible than the multidrug resistant variants to the effects of calcium channel blockers on cancer drug accumulation. This was shown for verapamil, nifedipine and the calmodulin inhibitor trifluoperazine acting on human, mouse and Chinese hamster ovary (CHO) cell lines. The enhancement of drug accumulation by calcium antagonists was similar to that caused by non-ionic detergents. Furthermore, verapamil was unable to alter 45Ca2+ accumulation in sensitive or resistant cells, suggesting that these agents act in a calcium-independent manner. Verapamil accumulation in multidrug resistant cells was reduced compared to sensitive cells. In spite of this reduced accumulation, however, verapamil alone was much more toxic to multidrug resistant cells than to the sensitive cells. This suggests that calcium channel blockers are specifically toxic to MDR cells by virtue of an interaction with the MDR cell surface distinct from that involved in promoting cellular accumulation.