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
View: Text | PDF
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

×

Figure 3

Inhibition of OATP1B2 with nilotinib protects against vincristine-induced peripheral neuropathy.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of OATP1B2 with nilotinib protects against vincristine-induce...
(A–C) Mechanical allodynia (A), thermal hyperalgesia (B), and sciatic nerve maximal action potential amplitudes (C) at baseline and 4 weeks (n = 6–7 per group) in WT mice or OATP1B2-deficient (OAP1B2–/–) mice receiving weekly i.p. injections of vincristine at a dose of 1 mg/kg (cumulative dose 4 mg/kg). Mice were pretreated with vehicle (hydroxypropyl methylcellulose) or nilotinib (100 mg/kg; p.o.) 30 minutes before every vincristine injection. Statistical analysis was performed using a 2-way ANOVA with Tukey’s post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (D) Light microscopy analysis of the sciatic nerve of WT mice and OATP1B2–/– mice receiving weekly vincristine (cumulative dose 4 mg/kg). Mice were pretreated with vehicle (hydroxypropyl methylcellulose) or nilotinib (100 mg/kg; p.o.) 30 minutes before every vincristine injection. After 4 weeks, vincristine-induced axonopathy (arrow) and fiber loss (circle) was evident. Nilotinib pretreatment and OATP1B2 deficiency protected against these morphologic changes. Magnification, 63×. Scale bar:20 μm. (E) Plasma concentration-time profile of vincristine (1 mg/kg) in WT mice or OATP1B2–/– mice pretreated with vehicle or nilotinib (100 mg/kg) (n = 7–9 per group). (F) DRG to plasma AUC ratio of vincristine (1 mg/kg) in WT mice or OATP1B2–/– mice pretreated with vehicle or nilotinib (100 mg/kg) (n = 3 per group). Statistical analysis was performed using 1-way ANOVA with Dunnett’s post hoc test. *P < 0.05, compared with WT mice pretreated with vehicle. Data are shown as mean ± SEM.