Enhancement of doxorubicin activity in multidrug-resistant cells by mefloquine.
We studied the effect of the antimalarial drug mefloquine on the resistance of K562 cells to doxorubicin. Mefloquine synergistically potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 0.5-3 microM, but had hardly any synergistic effect in the parental cell line (K562) at the same concentration. Mefloquine was more potent than verapamil, a known modulator of multidrug-resistance. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycoprotein, we evaluated the effect of mefloquine and of P-glycoprotein activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123. Our results indicate that mefloquine inhibits the P-glycoprotein pump-efflux activity in a dose-related manner. Moreover, mefloquine reduces the expression of the immunoreactive P-glycoprotein in K562/DXR cells as evaluated by cytofluorimetric assay. Taken together, the results indicate that mefloquine reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.
Fujita
R
R
Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, Sendai, Japan.
Ishikawa
M
M
Takayanagi
M
M
Takayanagi
Y
Y
Sasaki
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000345:Affinity Labels; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004396:Coloring Agents; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology*; D010641:Phenotype; D020112:Rhodamine 123; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000903:Antibiotics, Antineoplastic; D000962:Antimalarials; D001386:Azides; D002121:Calcium Channel Blockers; D004396:Coloring Agents; D004095:Dihydropyridines; D020112:Rhodamine 123; C041130:azidopine; D004317:Doxorubicin; D014700:Verapamil; D015767:Mefloquine