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Clin Transl Sci. 2017 Sep;10(5):412-420. doi: 10.1111/cts.12480. Epub 2017 Jul 8.

Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity.

Author information

1
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA.
6
Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.
7
Medical Clinic D, Experimental Nephrology, Münster Medical Faculty, Münster, Germany.
8
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Abstract

Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.

PMID:
28689374
PMCID:
PMC5593168
DOI:
10.1111/cts.12480
[Indexed for MEDLINE]
Free PMC Article

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