Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy

JCI Insight, 2023 · DOI: https://doi.org/10.1172/jci.insight.164646 · Published: July 24, 2023

Simple Explanation

The chemotherapy drug vincristine often causes nerve damage leading to tingling, numbness, pain, and sensitivity in the extremities. This study found that a specific protein, OATP1B3 in humans and OATP1B2 in mice, helps vincristine enter nerve cells. By blocking this protein in mice, researchers prevented nerve damage without reducing the drug's effectiveness against cancer. They used a drug called nilotinib to block OATP1B2. The study also identified a substance in the blood, α-tocopherol (a form of vitamin E), that can help measure how well OATP1B2 is working, potentially allowing doctors to adjust treatments to prevent nerve damage.

Study Duration

4 weeks

Participants

WT mice or OATP1B2 deficient mice (OATP1B2–/–) (8–12 weeks)

Evidence Level

Not specified

Key Findings

1
OATP1B3 (human) and OATP1B2 (mouse) are identified as neuronal transporters that regulate the uptake of vincristine into DRG neurons.
2
Genetic or pharmacological inhibition of OATP1B2 protected mice from VIPN hallmarks (mechanical allodynia, thermal hyperalgesia, changes in action potential) without affecting vincristine's plasma levels or antitumor effects.
3
α-tocopherol was identified as a circulating endogenous biomarker of neuronal OATP1B2 function, potentially guiding dose selection of OATP1B-type transport modulators to prevent VIPN.

Research Summary

This study identifies OATP1B-type transporters as mediators of vincristine uptake in DRG neurons and demonstrates that inhibiting these transporters can prevent VIPN. Genetic deficiency or pharmacological inhibition of OATP1B2 in mice protected against VIPN without compromising the antitumor properties of vincristine. α-tocopherol was identified as a biomarker of neuronal OATP1B-type transporter function, potentially serving as a companion diagnostic to optimize combinatorial regimens of OATP1B modulators and vincristine to prevent VIPN.

Practical Implications

Development of Transporter Inhibitors

The study provides a rationale for developing transporter inhibitors to mitigate vincristine-induced peripheral neuropathy, a debilitating side effect.

Personalized Medicine

α-tocopherol can serve as a companion diagnostic to guide dose selection of pharmacological inhibitors in combinatorial regimens with vincristine.

Drug Repurposing

Existing FDA-approved drugs like nilotinib, which inhibit OATP1B-type transporters, can be repurposed to prevent VIPN.

Study Limitations

1
The expression of OATP1B-type transporters was determined using whole DRG samples, a contribution of these transporters expressed in nonneuronal cell types, such as macrophages, cannot not be entirely excluded without a neuron-specific OATP1B2-KO model.
2
The behavioral methods used to study nociception here are somewhat subjective and warrant additional investigation to evaluate nonstimulus evoked nociception, such as place preference
3
The lack of pronounced morphological changes observed for the group treated with single-agent vincristine may be due to the relatively low dose used in our studies.

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