Reversal of Vinblastine Resistance in Human Leukemic Cells by Haloperidol and Dihydrohaloperidol.

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  • KATAOKA Yumi
    Department of Pharmacology and Pharmacy, Cancer Research Institute, Tohoku Pharmaceutical University
  • ISHIKAWA Masaaki
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University
  • MIURA Masatomo
    Department of Pharmacology and Pharmacy, Cancer Research Institute, Tohoku Pharmaceutical University
  • TAKESHITA Mitsuhiro
    Department of Pharmacology and Pharmacy, Cancer Research Institute, Tohoku Pharmaceutical University
  • FUJITA Ryousuke
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University
  • FURUSAWA Shinobu
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University
  • TAKAYANAGI Motoaki
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University
  • TAKAYANAGI Yoshio
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University
  • SASAKI Ken-ichi
    Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University

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Haloperidol, an antipsychotic, was investigated in cells overexpressing P-glycoprotein to detemine whether it was a clinically effective drug to reverse for reversing multidrug resistance (MDR) mediated by P-glycoprotein. A nontoxic concentration of haloperidol (1—30 μM) enhanced the cytotoxic effects of vinblastine (VBL) concentration-dependently in VBL-resistant human leukemia (K562/VBL) cells, but had no effect in the parent cells. Haloperidol also enhanced the cytotoxicities of epirubicin, doxorubicin and actinomycin 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 tumor line. Haloperidol increased the intracellular accumulation of VBL in the K562/VBL cells, and the binding of [3H]-azidopine to the cell-surface protein, P-glycoprotein, was inhibited by haloperidol in a concentration-dependent manner. Haloperidol was less potent than verapamil. Thus, haloperidol appeared to potentiate anticancer agents through the reversal of MDR by competitively inhibiting drug-binding to P-glyco-protein. In contrast, the main metabolite of haloperidol, dihydrohaloperidol, without antipsychotic activity, had less of an effect. Therefore, haloperidol might be useful in reversing drug-resistance.

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