Effect of PSC 833 on the cytotoxicity of idarubicin and idarubicinol in multidrug-resistant K562 cells.

We examined the effect of PSC 833, a non-immunosuppressive cyclosporin analogue, on the cytotoxicity, accumulation and retention of idarubicin (IDA) and its 13-dihydro metabolite, idarubicinol (IDAol). P-glycoprotein (PGP)-overexpressing multidrug-resistant K562/D1-9 cells were used for these studies. PSC 833 had no effect on the cytotoxicity, intracellular accumulation, or retention of IDA and IDAol in the parent K562 cells. However, intracellular accumulation of IDA and IDAol in K562/D1-9 cells after a 60-min incubation was restored by 0.4 microM PSC 833 to 104% and 116%, respectively, of the level in parent K562 cells. The retention of IDA and IDAol in K562/D1-9 cells was also restored by 0.4 microM PSC 833. Consequently, 0.4 microM PSC 833 increased the sensitivity of K562/D1-9 cells to IDA and IDAol. The resistance index (RI) of IDA decreased from 20-fold to 4.0-fold, and the RI of IDAol decreased from 104-fold to 1.5-fold. These results suggest that the combination of IDA and PSC 833 may be effective in reversing PGP-mediated multidrug resistance in leukemia cells.