Cyclosporin A and FK506 reverse anthracycline resistance by altering the cell cycle

We investigated the effect of cyclosporin A (CsA) or FK506 on the cytotoxicity of anthracyclines against a human laryngeal cancer cell line, KB cells, and a multi-drug resistance cell line, VJ-300 cells. CsA and FK506 enhanced the cytotoxicity of anthracyclines, especially in the VJ-300 cells. The intracellular concentrations of epirubicin (EPIR), daunomycin (DM), adriamycin (ADM) and THP-adriamycin (THP) were increased by the addition of CsA or FK506 in VJ-300, but not in KB cells. The intracellular accumulation of EPIR was most increased when CsA or FK506 was concomitantly administered with the drug. We also asked whether CsA or FK506 might influence the cycle of KB or VJ-300 cells. The population of cells in each phase of the cell cycle was little changed in both KB and VJ-300 cells when 0.3 microM ADM was administered for 24 h. Both CsA and FK506 significantly increased the ADM-induced accumulation of VJ-300 cells in G2M phase, in comparison with findings with KB cells. Thus, the reversal of MDR by CsA or FK506 is related to increased intracellular concentrations of cytotoxic drugs and, as a result, the increased G2M accumulates in MDR cells. Among of antrhacyclines, EPIR was most effective when concomitantly combined with CsA or FK506 in VJ-300 cells.