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J Clin Invest. 2018 Feb 1;128(2):816-825. doi: 10.1172/JCI96160. Epub 2018 Jan 16.

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity.

Author information

1
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
2
Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA.
3
Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
4
Division of Neuromuscular Disorders, Department of Neurology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
5
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
6
Department of Internal Medicine, College of Medicine, and.
7
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

Abstract

Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.

KEYWORDS:

Cancer; Oncology; Toxins/drugs/xenobiotics; Transport

PMID:
29337310
PMCID:
PMC5785270
DOI:
10.1172/JCI96160
[Indexed for MEDLINE]
Free PMC Article

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