Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy
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
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
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Research Article Oncology

Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy

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

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Figure 1

OATP1B2 deficiency attenuates vincristine-induced sensory peripheral neurotoxicity (VIPN).

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OATP1B2 deficiency attenuates vincristine-induced sensory peripheral neu...
(A) Intracellular accumulation of vincristine into HeLa cells overexpressing mouse (m), rat (r), or human (h) transporters, except for mOATP1B2, whose model was generated in HEK293 cells. Relative uptake is expressed as percentage change compared with empty vector controls (n = 4–14 per group). (B) Expression of the OATP1B1 and OATP1B3 genes in human whole DRG samples (pooled RNA from 21 male/female subjects), by reverse transcription PCR (RT-PCR) (depicted by the 154 bp product for OATP1B1 and 111 bp product for OATP1B3). Human OATP1B1 and OATP1B3 transporter–overexpressed cells were used as positive controls; empty vector controls were used as the negative control. LD, 100 bp ladder. (C–E) VIPN in WT mice or OATP1B2 deficient mice (OATP1B2–/–) at baseline and at 2, 3, and 4 weeks following weekly administrations of vincristine at a dose of 1 mg/kg (cumulative dose 4 mg/kg). Mechanical allodynia (C), thermal hyperalgesia (D), and sciatic nerve maximal action potential amplitudes (E) are expressed as percentage change relative to baseline values (n = 6–8 per group). Statistical analysis was performed using a 2-way ANOVA with Bonferroni’s post hoc test. **P < 0.01, ***P < 0.001, ****P < 0.0001, compared with baseline values. (F) Plasma concentration-time profile of vincristine (1 mg/kg) in WT mice or OATP1B2–/– mice (n = 4 per group). Data are shown as mean ± SEM.