Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs

The overexpression of P-glycoprotein (P-gp) and the multidrug resistance-as sociated protein (MRP) have been shown to confer broad drug resistance in t umor cells. We have demonstrated previously direct binding between MRP and a quinoline-based photoreactive drug (iodo-azido-amino quinoline, IAAQ) (Ve zmar et al., Biochem Biophys Res Commun 241: 104-111, 1997). In this report , we show the reversal of multidrug resistance in two MRP-overexpressing ce ll lines, HL60/AR and H69/AR, with four quinoline-based drugs. Non-toxic co ncentrations (5-20 mu M) of chloroquine, quinine, quinidine, and primaquine potentiated the toxicity of doxorubicin in a concentration-dependent manne r. These quinoline-based drugs showed a 5- to 10-fold decrease in the re, o f 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 f or H69/AR and HL60/AR, respectively. Moreover, using IAAQ, we showed that m olar excesses of chloroquine, quinine, quinidine, and MK-571 inhibit the ph otoaffinity labeling of MRP. Primaquine and vinblastine showed lesser inhib ition of MRP photoaffinity labeling by IAAQ. Taken together, the results of this study demonstrated the reversal of doxorubicin resistance with severa l quinoline-based drugs. Moreover, these drugs have been shown to reverse P -gp-mediated MDR and are clinically well tolerated. (C) 2000 Elsevier Scien ce Inc.