Abstract
The microtubule-stabilizing agent paclitaxel frequently leads to chemotherapy-induced peripheral neuropathy (CIN), which further increases the burden of disease and often necessitates treatment limitations. The pathophysiology of CIN appears to involve both “upstream” effects including altered intracellular calcium signaling and activation of calcium dependent proteases such as calpain as well as subsequent “downstream” neuro-inflammatory reactions with cytokine release and macrophage infiltration of dorsal root ganglia. In this study, we aimed to investigate whether these processes are linked by the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that paclitaxel exposure induced IL-6 synthesis in cultured sensory neurons from postnatal Wistar rats, which could be prevented by co-treatment with a calpain inhibitor. This suggests a calcium dependent process. We demonstrate that adult C57BL/6 mice deficient in IL-6 are protected from developing functional and histological changes of paclitaxel-induced neuropathy. Furthermore, pretreatment with an IL-6-neutralizing antibody resulted in the prevention of paclitaxel-induced neuropathy in C57BL/6 mice. Electrophysiological data from our preclinical model was adequately reflected by measurements of patients undergoing paclitaxel therapy for ovarian cancer. In this cohort, measured Il-6 levels correlated with the severity of neuropathy. Our findings demonstrate that IL-6 plays a pivotal role in the pathophysiology of paclitaxel-induced neuropathy per se and that pharmacological or genetic interference with this signaling pathway prevents the development of this potentially debilitating adverse effect. These findings provide a rationale for a clinical trial with IL-6 neutralizing antibodies to prevent dose-limiting neurotoxic adverse effects of paclitaxel chemotherapy.
Highlights
Chemotherapy-induced neuropathy (CIN) is among the most common adverse effects of chemotherapy and affects a large number of patients
Many patients suffering from CIN report allodynia, which in animals can be assessed by measuring the mechanical withdrawal threshold with the von Frey method
PTX treated WT animals developed a distinct reduction of sensory nerve action potential (SNAP) amplitude, but not Nerve conduction velocity (NCV), indicative of a sensory axonal neuropathy commonly found in CIN patients (two-way ANOVA, F(6, 72) = 4.151, p < 0.0001; Fig. 2a)
Summary
Chemotherapy-induced neuropathy (CIN) is among the most common adverse effects of chemotherapy and affects a large number of patients. Huehnchen et al Cell Death and Disease (2020)11:45 the development of CIN in general and neuropathic pain in particular (reviewed by Lees et al.[4]). Clinical studies demonstrated that increased levels of IL-6, respectively, soluble IL-6 receptor, correlated with painful CIN9 and patients receiving IL-6 neutralizing antibodies as part of their therapy reported less neuropathic pain compared with groups without these antibodies[10]. These findings are intriguing as IL-6 inhibition is being tested as an (additional) antiproliferative chemotherapy[11,12]. Inhibiting the IL-6 pathway may result in synergistic effects by (a) augmenting antiproliferative effects and (b) prevention of sensory neuropathy with subsequent dose-alterations
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