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Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B

¹ Medical and ² Basic Science Divisions, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ³ Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professionals, St. John's University, Jamaica, New York; and ⁴ Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Gary D. Kruh, University of Illinois at Chicago Cancer Center, 239 Medical Center Administration Building (M/C 700), 914 S. Wood Street, Chicago, IL 60612. Phone: 312-355-4226; Fax: 312-355-1085; E-mail: gkruh{at}uic.edu.

Key Words: transport • resistance • Ara-C • PMEA • epothilone B

Multidrug resistance protein 7 (MRP7; ABCC10) is an ATP-binding cassette transporter which is able to transport amphipathic anions and confer resistance to docetaxel and, to a lesser extent, vincristine and paclitaxel. Whereas some detail on the resistance profile of MRP7 is known, the activities of the pump have not been completely determined. Here, it is shown by the analysis of MRP7-transfected HEK293 cells that, in addition to natural product agents, MRP7 is also able to confer resistance to nucleoside-based agents, such as the anticancer agents cytarabine (Ara-C) and gemcitabine, and the antiviral agents 2',3'-dideoxycytidine and PMEA. Consistent with the operation of an efflux pump, expression of MRP7 reduced the accumulation of Ara-C and PMEA. In addition, MRP7 is also able to confer resistance to the microtubule-stabilizing agent epothilone B. Ectopic expression of MRP7 in mouse embryo fibroblasts deficient in P-glycoprotein and Mrp1 revealed that MRP7 has a broad resistance profile for natural product agents. In this drug-sensitive cellular background, MRP7 conferred high levels of resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), daunorubicin (7.5-fold), etoposide (11-fold), and vincristine (56-fold). Buthionine sulfoximine did not attenuate MRP7-conferred resistance to docetaxel or Ara-C. These experiments indicate that the resistance capabilities of MRP7 include nucleoside-based agents and a range of natural product anticancer agents that includes nontaxane antimicrotubule agents that are not susceptible to P-glycoprotein–mediated transport and that, unlike MRP1 and MRP2, MRP7-mediated drug transport does not involve glutathione. [Cancer Res 2009;69(1):178–84]