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

✍ Scribed by Gerrit J. Schuurhuis; Herbert M. Pinedo; Henricus J. Broxterman; Coenraad K. Van Kalken; Catharina M. Kuiper; Jan Lankelma

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: French
• Weight: 762 KB
• Volume: 46
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910460232

✦ Synopsis

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 I1-2933/001 was observed in the MDWsensitive cell couple CHRC,/AUXB,, probably due to a concentration-dependent stimulation of cell growth in the range of (u JLM cyclosporin A and of 1-4 JLM Ro I I-29331001. In partially revertant CHRC, cells, growth inhibition b Ro I I-29331001 at concentrations below I JLM, as seen in C H k , cells, changed into growth stimulation, and the collateral sensitivity to verapamil and bepridil disappeared almost completely. In the MDR cells CHRC,, 278VD and DC3F/DMXX, cross-resistance to another calcium channel blocking agent, Ro I1-1781/001 (tiapamil), was observed as well. This compound showed exceptional behavior: it induced marked potentiation of D x cytotoxicity as well as stimulation of Dx accumulation in AUXB, cells, even at low tiapamil concentrations, but not in the CHRC, 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.