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 4

Nilotinib as an adjunct to vincristine therapy.

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Nilotinib as an adjunct to vincristine therapy. (A) Expression of the hu...
(A) Expression of the human OATP1B1 and OATP1B3 genes in leukemia cells as measured by RT-PCR (depicted by the 154 bp product for OATP1B1 and 111 bp product for OATP1B3). HEK293 cells engineered to overexpress OATP1B1 or OATP1B3 were used as positive controls (denoted “Cell”), and cells transfected with an empty vector were used as negative controls (denoted “VC”). (B and C) Low OATP1B1 and OATP1B3 expression in malignant cells was confirmed in samples of 314 pediatric patients with acute myeloid leukemia (AML) (B) and 655 pediatric patients with B-lineage acute lymphoblastic leukemia (ALL) (C). Expression of the reduced folate carrier protein 1 (RFC1) was used as a reference gene in all samples. Median values in AML samples were RFC1 = 2.77, OATP1B1 = 0.00155, OATP1B3 = 0.00172; median values in ALL samples were RFC1 = 9.91, OATP1B1 = 0.00218, OATP1B3 = 0.00205. (D) Uptake of vincristine in leukemia cells in the presence or absence of nilotinib (1 μM) (n = 9 per group). Uptake data were normalized to total protein content. (E) Cytotoxicity of vincristine in leukemia cells in the presence or absence of nilotinib (1 μM). Cytotoxicity was measured by an MTT assay in 2-dimensional culture following continuous 72-hour exposure to vincristine (n = 9 per group). Data are shown as mean ± SEM. Statistical analysis was performed using a Student’s t test with Welch’s correction. (F) Proposed model of vincristine-induced injury to the peripheral nervous system in mice. Vincristine is taken up into cells within the peripheral nervous system by the transporter OATP1B2, ultimately leading to peripheral neuropathy, and these effects can be prevented by the OATP1B2 inhibitor nilotinib without negatively affecting anti-tumor efficacy.