The multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype) has been found to be modulated by racemic verapamil (through stimulation of glutathione transport), inducing apoptosis of human MRP1 cDNA-transfected baby hamster kidney 21 (BHK-21) cells and not of control BHK-21 cells. In this study, we show that the two enantiomers of verapamil have different effects on MRP1 activity. Only the S-isomer (not the R-isomer) potently induced the death of MRP1-transfected BHK-21 cells. The decrease in cellular glutathione content induced by the S-isomer, which was not observed with the R-isomer, was stronger than that induced by the racemic mixture, indicating that the R-isomer antagonized the S-isomer effect. Both enantiomers altered leukotriene C 4 and calcein transport by MRP1. Thus, the R-isomer behaved as an inhibitor, which was confirmed by its ability to revert the multidrug resistance phenotype toward vincristine. Molecular studies on purified MRP1 using fluorescence spectroscopy showed that both enantiomers bound to MRP1 with high affinity, with the binding being prevented by glutathione. Furthermore, conformational changes induced by the two enantiomers (monitored by sodium iodide accessibility of MRP1 tryptophan residues) were quite different, correlating with their distinct effects. (S)-Verapamil induces the death of potentially resistant tumor cells, whereas (R)-verapamil sensitizes MRP1-overexpressing cells to chemotherapeutics. These results might be of great potential interest in the design of new compounds able to modulate MRP1 in chemotherapy.Resistance of tumors to multiple structurally unrelated anticancer drugs is one of the major obstacles to successful cancer chemotherapy. Failure to achieve complete and long-lasting responses is a common clinical problem that limits the curative potential of anticancer drugs in clinical oncology. Human multidrug resistance (MDR) 2 is frequently associated with the overexpression of three transporters belonging to the ATP-binding cassette (ABC) protein superfamily, P-glycoprotein (ABCB1), the multidrug-resistance protein MRP1 (ABCC1), and the breast cancer resistance protein (ABCG2) (1), which can actively extrude anticancer drugs from the cell at the expense of ATP hydrolysis. MRP1 transports organic anions, many of which are conjugated to GSH, sulfate, or glucuronate; physiological substrates of MRP1 include GSH and leukotriene C 4 (LTC 4 ) (2). Cytotoxic drugs in clinical use against cancer such as vincristine, vinblastine, and daunorubicin are cotransported with GSH (2). Although a number of modulators have been found (3), the mechanism of inhibition is poorly understood. In many cases, a competitive inhibition toward substrate was described, as for the leukotriene antagonist MK571, which is considered a reference inhibitor for MRP1 (4). Interesting but complex results have been obtained with two classes of modulators: flavonoids and verapamil. Dietary flavonoids such as apigenin have been shown to interact with MRP1 (5), ...

Multidrug resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. It is able to transport a broad range of anticancer drugs through cellular membranes, thus limiting their antiproliferative action. Since its discovery in 1992, MRP1 has been the most studied among MRP proteins, which now count nine members. Besides the biological work, which targets structure elucidation, binding sites location, and mode of action, most efforts have been focused on finding molecules which act as MRP1 inhibitors. In this review, we attempt to summarize and highlight studies dealing with modulators of MRP1-mediated multidrug resistance (MDR), which have been accomplished in the last 5 years. The reported MRP1 inhibitors are discussed according to their chemical class. Finally, we try to bring information on structure-activity relationship (SAR) aspects and how modulators might interact with MRP1. This study may facilitate the rational design of future modulators of MDR.

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