Reversal of vinblastine resistance in human leukemic cells by haloperidol and dihydrohaloperidol

Haloperidol, an antipsychotic, was investigated in cells overexpressing P-g lycoprotein to determine whether it was a clinically effective drug to reve rse for reversing multidrug resistance (MDR) mediated by P-glycoprotein. A nontoxic concentration of haloperidol (1-30 mum) enhanced the cytotoxic eff ects of vinblastine (VBL) concentration-dependently in VBL-resistant human leukemia (K562/VBL) cells, but had no effect in the parent cells. Haloperid ol also enhanced the cytotoxicities of epirubicin, doxorubicin and actinomy cin D in the K562/VBL cells, but not those of idarubicin or cisplatin; this enhancement was less than that of the VBL, toxicity in the VBL-resistant t umor line. Haloperidol increased the intracellular accumulation of VBI. in the K562/VBL, cells, and the binding of [H-3]-azidopine to the cell-surface protein, P-glycoprotein, was inhibited by haloperidol in a concentration-d ependent manner. Haloperidol was less potent than verapamil. Thus, haloperi dol appeared to potentiate anticancer agents through the reversal of MDR by competitively inhibiting drug-binding to P-glycoprotein. In contrast, the main metabolite of haloperidol, dihydrohaloperidol, without antipsychotic a ctivity had less of an effect, Therefore, haloperidol might be useful in re versing drug-resistance.