Redox-sensitive TRP channels: a promising pharmacological target in chemotherapy-induced peripheral neuropathy

ABSTRACT

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain is a major side effect of certain chemotherapeutic agents used in cancer treatment. Available analgesics are mostly symptomatic, and on prolonged treatment, patients become refractive to them. Hence, the development of improved therapeutics that act on novel therapeutic targets is necessary. Potential targets include the redox-sensitive TRP channels [e.g. TRPA1, TRPC5, TRPC6, TRPM2, TRPM8, TRPV1, TRPV2, and TRPV4] which are activated under oxidative stress associated with CIPN.

Areas covered

We have examined numerous neuropathy-inducing cancer chemotherapeutics and their pathophysiological mechanisms. Oxidative stress and its downstream targets, the redox-sensitive TRP channels, together with their potential pharmacological modulators, are discussed. Finally, we reflect upon the barriers to getting new therapeutic approaches into the clinic. The literature search was conducted in PubMed upto and including April 2021.

Expert opinion

Redox-sensitive TRP channels are a promising target in CIPN. Pharmacological modulators of these channels have reduced pain in preclinical models and in clinical studies. Clinical scrutiny suggests that TRPA1, TRPM8, and TRPV1 are the most promising targets because of their pain-relieving potential. In addition to the analgesic effect, TRPV1 agonist-Capsaicin possesses a disease-modifying effect in CIPN through its restorative property in damaged sensory nerves.

KEYWORDS:

• Chemotherapy
• peripheral neuropathy
• neuropathic pain
• pathophysiological mechanisms
• oxidative stress
• redoxtrp
• pharmacotherapy
• chemotherapy-induced peripheral neuropathy
• cipn

Abbreviations

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Acknowledgements

We would like to acknowledge Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Government of India for providing the funding in the form of fellowships to carry out this review work in National Institute of Pharmaceutical Education and Research, S.A.S. Nagar.

Article Highlights

• Recently, redox sensitive TRP channels have gained importance in many redox-related diseases such as diabetes, cancer, neurodegeneration, and cardiovascular disease

• Redox TRPs can sense the redox environment and react appropriately to maintain homeostasis.

• Expression of redox TRPs is higher in peripheral nerves and is reported to change their expression patterns as CIPN progresses. Therefore, they act as a suitable pharmacological target.

• Pharmacological agents that target these channels hold therapeutic promise in CIPN

• Menthol (TRPM8 activator) and Capsaicin (TRPV1 agonist) are the most promising redox TRP channel modulators for treating CIPN.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.