The Role of Nucleotide Excision Repair in Cisplatin-Induced Peripheral Neuropathy: Mechanism, Prevention, and Treatment.

Scarlett Acklin,Fen Xia

doi:10.3390/ijms22041975

Abstract

Platinum-based chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting effects of cancer treatment and results in dose reduction and discontinuation of life-saving chemotherapy. Its debilitating effects are often permanent and lead to lifelong impairment of quality of life in cancer patients. While the mechanisms underlying the toxicity are not yet fully defined, dorsal root ganglia sensory neurons play an integral role in symptom development. DNA-platinum adducts accumulate in these cells and inhibit normal cellular function. Nucleotide excision repair (NER) is integral to the repair of platinum adducts, and proteins involved in its mechanism serve as potential targets for future therapeutics. This review aims to highlight NER’s role in cisplatin-induced peripheral neuropathy, summarize current clinical approaches to the toxicity, and discuss future perspectives for the prevention and treatment of CIPN.

Highlights

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Taxanes, proteasome/angiogenesis inhibitors, vinca alkaloids, and platinum-based drugs are the most common systemic anticancer treatments used as first-line chemotherapy for a variety of cancers, including breast, lung, colorectal and gastric cancers, and multiple myeloma [1]
Onset of the toxicity is expected to occur following cisplatin treatment at 250–350 mg/m2, and cumulative doses of 500–600 mg/m2 result in development of chemotherapy-induced peripheral neuropathy (CIPN) in almost all patients [8]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Patients may develop Lhermitte’s sign—an electric-shock-like sensation radiating cervico-caudally along the spine that can involve the arms, legs, or both and is provoked by neck flexion or rotation It has been described in patients with direct tumor involvement of the spinal cord, in relation to radiotherapy, and with cisplatin treatment, and is believed to result from a transient demyelination of the posterior columns [6]. Increasing evidence shows hypersensitivity to mechanical and thermal stimuli commonly develops after preferential damage to DRG sensory fibers This may be relevant to CIPN due, in part, to the lack of the blood-brain barrier in the peripheral nervous system and the consequent exposure of its neurons to endogenous and exogenous agents, such as metabolites, inflammatory molecules, and environmental contaminants. Preferential accumulation of cisplatin in the DRG results from the presence of an abundant fenestrated capillary network and the absence of the

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