Reversal of vinblastine resistance in human leukemic cells by haloperidol and dihydrohaloperidol.
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 microM) 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-glycoprotein. 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.
Kataoka
Y
Y
Department of Pharmacology and Pharmacy, Cancer Research Institute, Tohoku Pharmaceutical University, Sendai, Japan.
Ishikawa
M
M
Miura
M
M
Takeshita
M
M
Fujita
R
R
Furusawa
S
S
Takayanagi
M
M
Takayanagi
Y
Y
Sasaki
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry; D004095:Dihydropyridines / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006220:Haloperidol / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D019920:Photoaffinity Labels; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001386:Azides; D004095:Dihydropyridines; D019920:Photoaffinity Labels; C439203:dihydrohaloperidol; D014747:Vinblastine; C041130:azidopine; D006220:Haloperidol