Abstract
BackgroundOne of the major mechanisms that could produce resistance to antineoplastic drugs in cancer cells is the ATP binding cassette (ABC) transporters. The ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering the cytotoxic activity of antineoplastic drugs. One of these transporters, the multiple resistant protein 7 (MRP7, ABCC10), has recently been shown to produce resistance to antineoplastic drugs by increasing the efflux of paclitaxel. In this study, we examined the effects of BCR-Abl tyrosine kinase inhibitors imatinib, nilotinib and dasatinib on the activity and expression of MRP7 in HEK293 cells transfected with MRP7, designated HEK-MRP7-2.Methodology and/or Principal FindingsWe report for the first time that imatinib and nilotinib reversed MRP7-mediated multidrug resistance. Our MTT assay results indicated that MRP7 expression in HEK-MRP7-2 cells was not significantly altered by incubation with 5 µM of imatinib or nilotinib for up to 72 hours. In addition, imatinib and nilotinib (1-5 µM) produced a significant concentration-dependent reversal of MRP7-mediated multidrug resistance by enhancing the sensitivity of HEK-MRP7-2 cells to paclitaxel and vincristine. Imatinib and nilotinib, at 5 µM, significantly increased the accumulation of [3H]-paclitaxel in HEK-MRP7-2 cells. The incubation of the HEK-MRP7-2 cells with imatinib or nilotinib (5 µM) also significantly inhibited the efflux of paclitaxel.ConclusionsImatinib and nilotinib reverse MRP7-mediated paclitaxel resistance, most likely due to their inhibition of the efflux of paclitaxel via MRP7. These findings suggest that imatinib or nilotinib, in combination with other antineoplastic drugs, may be useful in the treatment of certain resistant cancers.
Highlights
The clinical use of surgery, radiation and chemotherapy have decreased the recurrence rates of cancer, cellular resistance to chemotherapeutic drugs is a major obstacle in the treatment of cancer [1,2]
Imatinib and nilotinib reverse MRP7-mediated paclitaxel resistance, most likely due to their inhibition of the efflux of paclitaxel via MRP7. These findings suggest that imatinib or nilotinib, in combination with other antineoplastic drugs, may be useful in the treatment of certain resistant cancers
We conducted Western blot experiments to determine if MRP1 and BCRP were expressed in HEK293pcDNA3.1 and HEK-MRP7-2 cells
Summary
The clinical use of surgery, radiation and chemotherapy have decreased the recurrence rates of cancer, cellular resistance to chemotherapeutic drugs is a major obstacle in the treatment of cancer [1,2]. Research strategies to circumvent such resistance in cancer cells have become a current focus for the development of novel combinational chemotherapeutic strategies Both intrinsic and acquired drug resistance can produce multiple changes in various cellular pathways, leading to a decrease in the cytotoxicity, and the efficacy, of antineoplastic drugs [3]. One of the primary cellular mechanisms that can produce resistance to antineoplastic therapy involves the efflux of drugs from the cancer cells by specific transmembrane transporters or pumps [4] These transporter proteins originate from the superfamily of ATP-binding cassette (ABC) transporters that share common structural and functional properties [5]. We examined the effects of BCR-Abl tyrosine kinase inhibitors imatinib, nilotinib and dasatinib on the activity and expression of MRP7 in HEK293 cells transfected with MRP7, designated HEK-MRP7-2
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