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Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B

Elizabeth Hopper-Borge1, Xiu Xu, Tong Shen

  • 1Medical and Basic Science Divisions, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Research
|January 2, 2009
PubMed

Insights

Multidrug resistance protein 7 (MRP7) confers resistance to anticancer drugs like docetaxel and nucleoside agents such as cytarabine. This efflux pump

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Cancer Research

Background:

  • Multidrug resistance protein 7 (MRP7; ABCC10) is an ATP-binding cassette transporter.
  • MRP7 confers resistance to certain chemotherapy drugs, but its full substrate profile is not well-defined.

Purpose of the Study:

  • To comprehensively characterize the drug resistance profile of MRP7.
  • To determine if MRP7 transports nucleoside-based agents and other natural products.

Main Methods:

  • Analysis of MRP7-transfected HEK293 cells.
  • Ectopic expression of MRP7 in drug-sensitive mouse embryo fibroblasts (deficient in P-glycoprotein and Mrp1).
  • Drug accumulation assays for cytarabine (Ara-C) and PMEA.
  • Assessment of resistance levels to various anticancer agents.

Main Results:

  • MRP7 confers resistance to nucleoside-based agents (cytarabine, gemcitabine) and antiviral nucleosides (2',3'-dideoxycytidine, PMEA).
  • MRP7 expression reduced the intracellular accumulation of Ara-C and PMEA, consistent with an efflux mechanism.
  • MRP7 demonstrated broad resistance to natural product anticancer agents, including high resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), and vincristine (56-fold).
  • Resistance to docetaxel and Ara-C was not affected by buthionine sulfoximine, indicating glutathione independence.

Conclusions:

  • MRP7 possesses a broad drug resistance profile, extending beyond known substrates to include nucleoside-based agents.
  • MRP7 mediates the transport of natural product anticancer agents, including non-taxane antimicrotubules, independent of P-glycoprotein.
  • MRP7-mediated drug transport does not involve glutathione, differentiating it from MRP1 and MRP2.

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