Endoplasmic Reticulum Stress in Chemotherapy-Induced Peripheral Neuropathy: Emerging Role of Phytochemicals

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting long-term sequela in cancer patients undergoing treatment, often leading to discontinuation of treatment. No established therapy exists to prevent and/or ameliorate CIPN. Reactive oxygen species (ROS) and mitochondrial dysregulation have been proposed to underlie the pathobiology of CIPN. However, interventions to prevent and treat CIPN are largely ineffective. Additional factors and mechanism-based targets need to be identified to develop novel strategies to target CIPN. The role of oxidative stress appears to be central, but the contribution of endoplasmic reticulum (ER) stress remains under-examined in the pathobiology of CIPN. This review describes the significance of ER stress and its contribution to CIPN, the protective role of herbal agents in countering ER stress in nervous system-associated disorders, and their possible repurposing for preventing CIPN.

Keywords: cancer; chemotherapy; endoplasmic reticulum stress; neuropathy; oxidative stress; pain; phytochemicals.

Figure 1

Endoplasmic reticulum stress contributes to chemotherapy-induced peripheral neuropathy. Normal functions of ER include protein synthesis, maturation, and the folding of proteins and transport. Disturbance of these functions by chemotherapy may induce ER stress to kill tumor cells, resulting in the accumulation of misfolded proteins. ER stress leads to the activation of unfolded protein response (UPR) via UPR sensors: ATF6α, IRE1α, and PERK. This further activates signaling pathways as adaptive response to reduce the protein misfolding. The UPR enhances the ER capacity for protein folding and modification, attenuates global mRNA translation, and disposes misfolded proteins by ER-associated protein degradation (ERAD) and autophagy. If ER stress persists, the UPR triggers cell death. ROS are generated as a byproduct of oxidative protein folding catalyzed by ER oxidoreductases, including protein disulfide isomerases (PDI). Accumulated misfolded proteins increase the protein-folding load and consume the antioxidant reserve in the cell. Mitochondrial ROS are generated by calcium-enhanced ER release. Elevated Ca²⁺ levels in the mitochondria cause the release of cytochrome c and subsequently trigger death signals via caspase activation. Together, these processes may cause neural injury, leading to neuropathic symptoms of chemotherapy. Abbreviations: ATF6α: activating transcription factor 6α, Ca²⁺: calcium ion, ER: endoplasmic reticulum. ERAD: ER-associated protein degradation IRE1α: inositol requiring enzyme 1α, MPs: misfolded protein, PDI: protein disulfide isomerases PERK: protein kinase RNA-activated-like ER kinase ROS: Reactive Oxygen Species, UP: unfolded protein, UPR: unfolded protein response.