Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs.
The overexpression of P-glycoprotein (P-gp) and the multidrug resistance-associated protein (MRP) have been shown to confer broad drug resistance in tumor cells. We have demonstrated previously direct binding between MRP and a quinoline-based photoreactive drug (iodo-azido-amino quinoline, IAAQ) (Vezmar et al., Biochem Biophys Res Commun 241: 104-111, 1997). In this report, we show the reversal of multidrug resistance in two MRP-overexpressing cell lines, HL60/AR and H69/AR, with four quinoline-based drugs. Non-toxic concentrations (5-20 microM) of chloroquine, quinine, quinidine, and primaquine potentiated the toxicity of doxorubicin in a concentration-dependent manner. These quinoline-based drugs showed a 5- to 10-fold decrease in the IC(50) of doxorubicin in H69/AR and HL60/AR cells. Primaquine was the most active, with modulation ratios of 10- and 5-fold versus 8- and 3-fold with MK-571 for H69/AR and HL60/AR, respectively. Moreover, using IAAQ, we showed that molar excesses of chloroquine, quinine, quinidine, and MK-571 inhibit the photoaffinity labeling of MRP. Primaquine and vinblastine showed lesser inhibition of MRP photoaffinity labeling by IAAQ. Taken together, the results of this study demonstrated the reversal of doxorubicin resistance with several quinoline-based drugs. Moreover, these drugs have been shown to reverse P-gp-mediated MDR and are clinically well tolerated.
Vezmar
M
M
Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada.
Georges
E
E
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002738:Chloroquine; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines