Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line.
We studied the restoration of doxorubicin accumulation and sensitivity by verapamil and quinine in a variant of the human erythroleukemia cell line K562 selected for resistance to doxorubicin and presenting a multidrug-resistance (MDR) phenotype. Verapamil was able to completely restore doxorubicin accumulation in the resistant cells to the level obtained in sensitive cells, but only partially reversed doxorubicin resistance. Quinine, in contrast, had a relatively weak effect on doxorubicin accumulation but was able to completely restore doxorubicin sensitivity in the resistant cells. In addition, verapamil was able to decrease azidopine binding to P-glycoprotein, whereas quinine was not. Quinine also modified the intracellular tolerance to doxorubicin, which suggests that it is able to modify drug distribution within the cells. Confocal microscopy revealed that verapamil and quinine were able to restore nuclear fluorescence staining of doxorubicin in resistant cells; since this was obtained for quinine without significant increase of doxorubicin accumulation, this observation confirms that quinine acts principally on doxorubicin redistribution within the cells, allowing the drug to reach its nuclear targets. When used in association, verapamil and quinine reversed doxorubicin resistance in a synergistic fashion. We conclude that verapamil and quinine do not share the same targets for reversal of MDR in this cell line; whereas verapamil directly interferes with P-glycoprotein and mainly governs drug accumulation, quinine has essentially intracellular targets involved in drug redistribution from sequestration compartments.
Bennis
S
S
Institut Bergonie, Université de Bordeaux II, France.
Ichas
F
F
Robert
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000345:Affinity Labels / Q000378:metabolism; D001386:Azides / Q000037:antagonists & inhibitors / Q000378:metabolism; D004095:Dihydropyridines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010641:Phenotype; D011803:Quinine / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; C041130:azidopine; D004317:Doxorubicin; D011803:Quinine; D014700:Verapamil