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MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid
Author(s) -
Huisman Maarten T.,
Chhatta Aniska A.,
van Tellingen Olaf,
Beijnen Jos H.,
Schinkel Alfred H.
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21013
Subject(s) - multidrug resistance associated protein 2 , probenecid , pharmacology , abcg2 , paclitaxel , taxane , atp binding cassette transporter , abcc1 , docetaxel , p glycoprotein , multiple drug resistance , transporter , drug resistance , chemistry , medicine , biology , chemotherapy , cancer , biochemistry , breast cancer , microbiology and biotechnology , gene
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. © 2005 Wiley‐Liss, Inc.