OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
Alix F. Leblanc, … , Alex Sparreboom, Shuiying Hu
Alix F. Leblanc, … , Alex Sparreboom, Shuiying Hu
Published February 1, 2018; First published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):816-825. https://doi.org/10.1172/JCI96160.
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Categories: Research Article Oncology

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

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.

Authors

Alix F. Leblanc, Jason A. Sprowl, Paola Alberti, Alessia Chiorazzi, W. David Arnold, Alice A. Gibson, Kristen W. Hong, Marissa S. Pioso, Mingqing Chen, Kevin M. Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H. Mathijssen, Raquel E. Reinbolt, Maryam B. Lustberg, Lara E. Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu

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Figure 1

Phenotypic characterization of OATP1B2–/– mice.

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Phenotypic characterization of OATP1B2–/– mice. (A) Comparative expressi...
(A) Comparative expression of OATP1B2 protein in liver and DRG at baseline of wild-type (WT) and OATP1B2–/– (–/–). (B) Detection of OATP1B2 by immunofluorescence in DRG of wild-type and OATP1B2–/– mice. OATP1B2 is depicted by yellow fluorescence, whereas DNA is depicted in blue (DAPI). Scale bars: 50 μm. (C) Comparative expression of 84 transporter genes in DRG at baseline of wild-type and OATP1B2–/– mice (n = 3 samples per group). Each symbol represents an average reading for a single gene, the solid line is the line of identity, and the dotted lines represent the 95% confidence intervals. The colored symbol represents the transporter gene for OATP2B1 (SLCO2B1). (D) Lack of paclitaxel transport by OATP2B1 in HEK293 cells transfected with an empty vector (VC) or OATP2B1 (2.5 μM; 5-minute incubations). Overexpression of the transporter was confirmed by evaluating the uptake of estrone-3-sulfate (E2S). Data represent the mean of triplicate observations from experiments performed on 2 separate occasions, and are expressed as average percentage of uptake values in cells transfected with an empty vector (VC) with error bars representing SD. *Denotes significant differences from VC (P < 0.05), and NS denotes not significant, as evaluated with an unpaired 2-sided Student’s t test with Welch’s correction.