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 5

Identification of a DRG-specific endogenous biomarker of OATP1B2.

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Identification of a DRG-specific endogenous biomarker of OATP1B2. (A) Sc...
(A) Schematic overview of the untargeted metabolomics screen to discover an endogenous biomarker of OATP1B2. (B) Volcano plot of differentially endogenous metabolites in untreated plasma of WT mice or OATP1B2-deficient (OATP1B2–/–) mice. Positive fold change indicates higher plasma concentration in OATP1B2–/– mice (n = 6 per group). Dotted lines indicate a log10 P value threshold of > 1.3 and a log2FC (fold change) of ± 0.2. (C) Volcano plot of differentially endogenous metabolites in untreated whole DRG samples of WT mice or OATP1B2–/– mice. Negative fold change indicates lower DRG levels in OATP1B2–/– mice (n = 6 per group). (D) Plasma levels and DRG/plasma ratios of α-tocopherol in WT mice or OATP1B2–/– mice in secondary validation studies. Statistical analysis was performed using an unpaired 2-tailed Student’s t test with Welch’s correction. ***P < 0.001 (n = 6 per group). (E) Relative DRG/plasma ratio of α-tocopherol in WT mice or OATP1B2–/– mice 2 hours after the administration of vehicle control (hydroxypropyl methylcellulose), rifampin (20 mg/kg; i.p.), or nilotinib (100 mg/kg; p.o.). Data are normalized to baseline levels observed in WT mice (n = 3 per group). Statistical analysis was performed using 1-way ANOVA with Dunnett’s post hoc test. ****P < 0.0001.