Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of several anti-neoplastics and a main cause of sensory disturbances in cancer survivors, negatively impacting patients’ quality of life. Peripheral nerve degeneration or small fibre neuropathy is generally accepted as the underlying mechanism in the development of CIPN. Recent evidence has contributed to clarify the determinant role of cytokines and chemokines in the process leading to neuronal hyperexcitability. Exposure to oxaliplatin triggers alterations in peripheral neuropathic pathways previously linked to IL-8 pathway. We investigated a novel selective inhibitor of IL-8 receptors, DF2726A, and showed its effects in counteracting CINP pathways, extending the relevance of the activation of IL-8 pathway to the class of platinum chemotherapeutics. Based on our results, we suggest that DF2726A might be a promising candidate for clinical treatment of CIPN conditions due to its efficacy and optimized pharmacokinetic/pharmacodynamic profile.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is side effect of different anti-cancer drugs resulting in sensory illness in cancer patients, affecting the patients quality of life[1,2]
Peripheral neuropathy is generally recognized as the main mechanism in the development of CIPN6,7, but different reports indicate that neuropathic pain caused by anti-cancer drugs may develop as early as the first treatment in the absence of to intra-epidermal nerve fibres (IENFs) damage or peripheric axonal degeneration[8,9]
In vitro pharmacological characterization showed that DF2726A did not inhibit spontaneous human polimorphonuclear neutrophil migration per se, but was efficacious in inhibiting IL-8- and CXCL1-induced hPMN chemotaxis with IC50 values calculated in 10 ± 5 nM and 8 ± 3 nM for IL-8 and CXCL1, respectively
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is side effect of different anti-cancer drugs resulting in sensory illness in cancer patients, affecting the patients quality of life[1,2]. Peripheral neuropathy is generally recognized as the main mechanism in the development of CIPN6,7, but different reports indicate that neuropathic pain caused by anti-cancer drugs may develop as early as the first treatment in the absence of to intra-epidermal nerve fibres (IENFs) damage or peripheric axonal degeneration[8,9]. Recent evidence has contributed to elucidate the determinant role of cytokines and chemokines in the process leading to neuronal hyperexcitability Exposure to chemotherapeutics such as paclitaxel[10] and oxaliplatin[7] consistently increased secretion of pro-inflammatory cytokines (TNFα, IL-1β and IL-6) and downregulated anti-inflammatory cytokines (IL-10 and IL-4) in spinal astrocytes and dorsal root ganglia (DRGs), triggering alterations in peripheral neuropathic pathways. A very recent report described the induction of CCL2/CCR2 pathway in oxaliplatin-induced DRGs, increasing mechanical and cold allodynia, and hypersensitivity of spinal astrocytes[14]. Several other studies found that both paclitaxel and oxaliplatin induced analogous mechanisms in the pathogenesis of neuropathic pain including spinal astrocyte activation, loss of IENFs, and mechanical and cold hypersensitivity[15,16,17]
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