Elsevier

Biochemical Pharmacology

Volume 59, Issue 10, 15 May 2000, Pages 1245-1252
Biochemical Pharmacology

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

https://doi.org/10.1016/S0006-2952(00)00270-7Get rights and content

Abstract

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 μM) 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 ic50 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.

Section snippets

Materials

Iodine-125 (100.7 mCi/mL) was purchased from Amersham Biochemical Inc. LTC4 was purchased from the Cayman Chemical Co. The SCLC cells (H69 and H69/AR) were gifts from Dr. Susan P. C. Cole (Cancer Research Laboratories). The HL60 and HL60/AR cells were gifts from Dr. M. Center at Kansas State University. All other chemicals were of the highest commercial grade available.

Cell culture and plasma membrane preparation

Drug-sensitive (H69 and HL60) and -resistant (H69/AR and HL60/AR) cells were grown in RPMI 1640 medium containing 4 mM

Reversal of MRP-mediated MDR with quinoline-based drugs

Gene transfer studies have now confirmed the role of MRP in MDR in vitro13, 15. Furthermore, there is increasing evidence for the role of MRP in drug-resistant cancers 25, 27, 28, 29. However, as MRP-mediated MDR is not reversed effectively by P-gp inhibitors, there is a need to identify drugs that can reverse MRP-mediated MDR 36, 37. We have demonstrated previously direct interaction between MRP and a quinoline-based photoreactive drug (IAAQ) [44]. The photoaffinity labeling of MRP with IAAQ

Acknowledgements

The authors would like to thank Joel Karwatski for his critical reading of the manuscript. This work was supported by a grant from the Natural Science and Engineering Research Council of Canada (NSERC) to E.G. Research at the Institute of Parasitology is partially supported by the Fonds FCAR pour l’aide à la recherche.

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