Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting neurotoxic effect of chemotherapy, is the most common reason for early cessation of cancer treatment. This can result in an increased risk of recurrence and decreased survival rate. Inflammatory cascade activation, proinflammatory cytokine upregulation, and neuro-immune communication pathways play essential roles in the initiation and progression of CIPN. Most notably, TNF-α, IL-1β, IL-6, and CCL2 are involved in neuropathic pain. Further elucidation of the role of these cytokines could lead to their development and use as biomarkers for predicting the onset of painful peripheral neuropathy and early axonal damage. In this review, we provide evidence for the involvement of cytokines in CIPN, the possible underlying mechanisms, and their use as potential therapeutic targets and biomarkers to prevent and improve the painful peripheral neuropathy related to chemotherapeutic agents.

Figure 1

The proposed targets of chemotherapy-induced neurotoxicity in the peripheral nervous system.

Figure 2

A proposed diagram of cytokine network in pathogenesis of chemotherapy-induced peripheral neuropathic pain. Chemotherapeutic drugs such as taxanes induce upregulation of Matrix metalloproteinases (MMPs) in Schwann cells, DRGs and peripheral nerves. MMPs exert the following different roles in the pathogenesis of chemotherapy-induced peripheral neuropathy: 1) MMPs are the only proteases able to degrade the blood-nerve-barrier (BNB) by disruption of extracellular matrix components of the basement membrane; 2) MMPs directly degrade the myelin sheath; 3) MMPs induce migration, infiltration and activation of inflammatory cells in DRG and peripheral nerves; 4) MMPs induce inflammatory cells to release and activate inflammatory cytokines IL-6, IL-8, IL1B, TNF-a. The latter directly or indirectly act on primary afferent neurons to induce hypersensitivity of peripheral nerves, which contribute to the peripheral neuropathic pain processing after chemotherapy infusion.