title: MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid.
abstract: ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor.
authors.affiliation: Division of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Maarten T
authors.initials: MT
authors.lastname: Huisman
authors.forename: Aniska A
authors.initials: AA
authors.lastname: Chhatta
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D000077143:Docetaxel; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins / Q000502:physiology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D011339:Probenecid / Q000493:pharmacokinetics / Q000494:pharmacology*; D043823:Taxoids / Q000493:pharmacokinetics; D014747:Vinblastine / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D005047:Etoposide; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D011339:Probenecid; D043823:Taxoids; D014747:Vinblastine; C000715087:ABCC2 protein, human