CXCR1/2 pathways in paclitaxel-induced neuropathic pain

Abstract

// Brandolini Laura 1, * , Benedetti Elisabetta 2, * , Ruffini Pier Adelchi 3 , Russo Roberto 4 , Cristiano Loredana 2 , Antonosante Andrea 2 , d’Angelo Michele 2 , Castelli Vanessa 2 , Giordano Antonio 5, 6 , Allegretti Marcello 1 , Cimini Annamaria 2, 6, 7 1 Dompé Farmaceutici SpA, Via Campo di Pile, L’Aquila, Italy 2 Department of Life, Health and Environmental Sciences, University of L’Aquila, Italy 3 Dompé Farmaceutici SpA, Via Santa Lucia, Milano, Italy 4 Department of Pharmacy, University of Naples Federico II, Italy 5 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy 6 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, USA 7 National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy * These authors contributed equally to this work Correspondence to: Allegretti Marcello, email: marcello.allegretti@dompe.com Keywords: chronic pain, chemotherapy, microtubules, IL-8, CXCR1/2 inhibitor Received: January 04, 2017      Accepted: February 08, 2017      Published: February 20, 2017 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.