Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10).
BACKGROUND
One 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.
We 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 microM of imatinib or nilotinib for up to 72 hours. In addition, imatinib and nilotinib (1-5 microM) 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 microM, significantly increased the accumulation of [(3)H]-paclitaxel in HEK-MRP7-2 cells. The incubation of the HEK-MRP7-2 cells with imatinib or nilotinib (5 microM) also significantly inhibited the efflux of paclitaxel.


CONCLUSIONS
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.
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, New York, United States of America.
Tong
T
Shen
Ye-Hong
YH
Kuang
Charles R
CR
Ashby
Yu
Y
Lei
Angel
A
Chen
Ying
Y
Zhou
Xiang
X
Chen
Amit K
AK
Tiwari
Elizabeth
E
Hopper-Borge
Jiangyong
J
Ouyang
Zhe-Sheng
ZS
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008956:Models, Chemical; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D010879:Piperazines; D011743:Pyrimidines; D013778:Tetrazolium Salts; D013844:Thiazoles; C421142:ABCC10 protein, human; C022616:thiazolyl blue; C498826:nilotinib