CXCR1/2 pathways in paclitaxel-induced neuropathic pain
Metrics: PDF 1532 views | HTML 1765 views | ?
Brandolini Laura1,*, Benedetti Elisabetta2,*, Ruffini Pier Adelchi3, Russo Roberto4, Cristiano Loredana2, Antonosante Andrea2, d’Angelo Michele2, Castelli Vanessa2, Giordano Antonio5,6, Allegretti Marcello1, Cimini Annamaria2,6,7
1Dompé Farmaceutici SpA, Via Campo di Pile, L’Aquila, Italy
2Department of Life, Health and Environmental Sciences, University of L’Aquila, Italy
3Dompé Farmaceutici SpA, Via Santa Lucia, Milano, Italy
4Department of Pharmacy, University of Naples Federico II, Italy
5Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
6Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, USA
7National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy
*These authors contributed equally to this work
Allegretti Marcello, email: firstname.lastname@example.org
Keywords: chronic pain, chemotherapy, microtubules, IL-8, CXCR1/2 inhibitor
Received: January 04, 2017 Accepted: February 08, 2017 Published: February 20, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.