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 anal ogue, on the cytotoxicity, accumulation and retention of idarubicin (IDA) a nd its 13-dihydro metabolite, idarubicinol (IDAol). P-glycoprotein (PGP)-ov erexpressing multidrug-resistant K562/D1-9 cells were used for these studie s. PSC 833 had no effect on the cytotoxicity, intracellular accumulation, o r retention of IDA and IDAol in the parent K562 cells. However, intracellul ar accumulation of IDA and IDAol in K562/D1-9 cells after a 60-min incubati on was restored by 0.4 mu M PSC 833 to 104% and 116%, respectively, of the level in parent K562 cells. The retention of IDA and IDAol in K562/D1-9 cel ls was also restored by 0.4 mu M PSC 833. Consequently, 0.4 mu M PSC 833 in creased 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 combina tion of IDA and PSC 833 may be effective in reversing PGP-mediated multidru g resistance in leukemia cells. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.