Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy

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Abstract

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN — including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology — without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.

Authors

Yang Li, Thomas Drabison, Mahesh Nepal, Richard H. Ho, Alix F. Leblanc, Alice A. Gibson, Yan Jin, Wenjian Yang, Kevin M. Huang, Muhammad Erfan Uddin, Mingqing Chen, Duncan F. DiGiacomo, Xihui Chen, Sobia Razzaq, Jeffrey R. Tonniges, Dana M. McTigue, Alice S. Mims, Maryam B. Lustberg, Yijia Wang, Amanda B. Hummon, William E. Evans, Sharyn D. Baker, Guido Cavaletti, Alex Sparreboom, Shuiying Hu