Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling side effect of many anticancer drugs [1]
Reparixin antinociceptive effect was visible over the time-course corresponding to drug delivery by microwww.impactjournals.com/oncotarget osmotic pump; the activity disappeared after the end of drug delivery by pump, indicating that the observed protection is strictly correlated to drug administration and action
CIPN is a common and potentially severe adverse effect associated with Microtubule-stabilizing agents (MTSAs) therapy [31] and taxaneinduced neuropathy is by far the most extensively investigated in preclinical and clinical studies
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling side effect of many anticancer drugs [1]. Www.impactjournals.com/oncotarget at 6 months [3] With such a high prevalence of disease, CIPN has important clinical implications significantly impacting the quality of life and often resulting in treatment discontinuation, which may affect overall survival [4, 2]. The pathogenesis of CIPN has not been fully elucidated but it is noteworthy that the overall neuropathy symptom profile appears to be substantially shared across different classes of chemotherapeutic agents including taxanes, platinum, proteasome inhibitors, and vinca-alkaloids. Peripheral nerve degeneration or small fiber neuropathy is generally accepted as the underlying mechanism in the development of CIPN [6,7] but several studies point out that neuropathic pain caused by anticancer agents may occur early after the first infusion in the absence of damage to intra-epidermal nerve fibers or axonal degeneration in peripheral nerves [8,9]
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