Differential sensitivity of multi-drug-resistant and -sensitive cells to resistance-modifying agents and the relation with reversal of anthracycline resistance

Calcium channel blockers, calmodulin inhibitors, and some other classes of non-related compounds reverse multi-drug resistance. In the present study, we found that several resistance modifiers are more toxic for MDR cells than for the corresponding sensitive parent cells, whereas others show the opposite effect. Several calcium channel blockers including bepridil, diltiazem, nifedipine and verapamil, as well as the calmodulin inhibitor trifluoperazine, were more toxic for several MDR cell lines than for the parent cell lines. In contrast, cross-resistance for cyclosporin A and the verapamil analogue Ro 11-2933/001 was observed in the MDR/sensitive cell couple CH(R)C₅/AUXB₁, probably due to a concentration-dependent stimulation of cell growth in the range of 0-4 μM cyclosporin A and of 1-4 μM Ro 11-2933/001. In partially revertant CH(R)C₅ cells, growth inhibition by Ro 11-2933/001 at concentrations below 1 μM, as seen in CH(R)C₅ cells, changed into growth stimulation, and the collateral sensitivity to verapamil and bepridil disappeared almost completely. In the MDR cells CH(R)C₅, 2780(AD) and DC3F/DMXX, cross-resistance to another calcium channel blocking agent, Ro 11-1781/001 (tiapamil), was observed as well. This compound showed exceptional behavior: it induced marked potentiation of Dx cytotoxicity as well as stimulation of Dx accumulation in AUXB₁ cells, even at low tiapamil concentrations, but not in the CH(R)C₅ cells, even at high concentrations. It is concluded that resistance modifiers can selectively influence growth of MDR cells via more than one process, and resulting in either strong growth inhibition in MDR cells relative to the effect on sensitive cells or in growth stimulation.