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Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs
1Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada.
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 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.
Insights
Several quinoline-based drugs, including primaquine, reverse multidrug resistance (MDR) in cancer cells by inhibiting P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP). These drugs are well-tolerated and potentiate chemotherapy effectiveness.
Area of Science:
- Pharmacology
- Cancer Biology
- Drug Resistance
Background:
- Overexpression of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) leads to broad drug resistance in tumor cells.
- Previous studies demonstrated direct binding between MRP and iodo-azido-amino quinoline (IAAQ).
Purpose of the Study:
- To investigate the reversal of multidrug resistance in MRP-overexpressing cell lines using quinoline-based drugs.
- To evaluate the efficacy of chloroquine, quinine, quinidine, and primaquine in potentiating doxorubicin toxicity.
Main Methods:
- Testing four quinoline-based drugs (chloroquine, quinine, quinidine, primaquine) on HL60/AR and H69/AR cell lines.
- Assessing the potentiation of doxorubicin toxicity and measuring IC(50) values.
- Using IAAQ to study the inhibition of MRP photoaffinity labeling by these drugs.
Main Results:
- Non-toxic concentrations of chloroquine, quinine, quinidine, and primaquine reversed doxorubicin resistance in MRP-overexpressing cells.
- Primaquine showed the highest activity, with significant modulation ratios compared to MK-571.
- These quinoline drugs inhibited the photoaffinity labeling of MRP by IAAQ, indicating interaction.
Conclusions:
- Several quinoline-based drugs effectively reverse doxorubicin resistance mediated by MRP.
- These drugs also demonstrate efficacy against P-gp-mediated multidrug resistance (MDR).
- The tested quinoline-based drugs are clinically well-tolerated, suggesting potential therapeutic applications.
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