Synergistic effect of cyclosporin A and verapamil in overcoming vincristine resistance of multidrug-resistant cultured human leukemia cells.

Reversal of vincristine (VCR) resistance by cyclosporin A (CyA) or the combination of CyA and verapamil (VER) was investigated by using four P-glycoprotein (P-gp)-associated human multidrug-resistant (MDR) cell lines (K562/ADM, KYO-1, HEL and CMK). Drug sensitivity was expressed as 50% inhibitory concentration (IC50). The degree of reversal of resistance was expressed as x-fold decrease by dividing the IC50 value without modifier(s) by that with modifier(s). CyA overcame P-gp-associated MDR significantly in all four MDR cell lines. Reversal of VCR resistance by CyA appeared to be dose-dependent. In the case of low-grade MDR cell lines (KYO-1, HEL and CMK), CyA at the low concentration of 0.5 microgram/ml was still effective. The degree of reversal of VCR resistance in this condition was greater (6.3- to 16-fold decrease) in the low-grade MDR cell lines than in a high-grade MDR cell line (K562/ADM) (2.9-fold decrease). At a high concentration (5 micrograms/ml) of CyA, however, it was greater (240-fold decrease) in the high-grade MDR cell lines than in the low-grade MDR cell line (20- to 100-fold decrease). This indicates that concentration of CyA required for overcoming drug resistance in MDR cells was dependent on the degree of drug resistance. CyA overcame VCR resistance more efficiently than VER. The combination of CyA and VER enhanced reversal of VCR resistance in a supra-additive or at least an additive manner and overcame VCR resistance at low concentrations of both modifiers that are clinically achievable with safety.