CXCR1/2 pathways in paclitaxel-induced neuropathic pain

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.

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2–Negative Metastatic Breast Cancer

“…Interestingly, a low incidence and severity of grade 3 and 4 peripheral neuropathy was observed compared with published studies with weekly paclitaxel [25]. A possible role of reparixin in reducing this common adverse reaction to paclitaxel is being investigated in experimental models [26]. …”

Wen-Luo-Tong Decoction Attenuates Paclitaxel-Induced Peripheral Neuropathy by Regulating Linoleic Acid and Glycerophospholipid Metabolism Pathways

“…Caspase signaling is also found to contribute to PIPN, leading to the generation of reactive oxygen species (ROS), as well as potential apoptosis (Park et al, 2004 ). Additionally, pathways activate inflammatory cytokines, such as TNF-α, MAPK, and CX3CL1, are involved with CIPN as well (Cavaletti et al, 2000 ; Zhang et al, 2010 ; Brandolini et al, 2017 ). Moreover, recent evidences indicated that activation of TRPV1 during chemotherapy sensitizes pain pathways.…”

Probiotic DSF counteracts chemotherapy induced neuropathic pain

“…On the other hand, low dose of Paclitaxel produces hypersensitivity pain including allodynia and hyperalgesia. Neurotoxicity caused by Paclitaxel is attributed to alteration of microtubule structure leading to increased microtubule stability by increasing acetylated α-tubulin causing neuropathic pain, but it has been recently indicated that Paclitaxel triggers the activation of IL-8 signaling in DRG neurons in culture [ 21 ].…”

“…In this work, we wanted to test the hypothesis that Paclitaxel-induced neuropathic pain can be counteracted by the probiotic formulation of DSF. To this purpose, the biomolecular pathways involved in chemotherapy induced peripheral neuropathy, already described by us in a previous work [ 21 ], were investigated.…”