CXCR1/2 pathways in paclitaxel-induced neuropathic pain.
CXCR1/2 pathways in paclitaxel-induced neuropathic pain.
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DOI：
10.18632/oncotarget.15533
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发表时间：
2017-04-04
期刊：
影响因子：
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通讯作者：
Cimini A
中科院分区：
文献类型：
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作者：
Brandolini L;Benedetti E;Ruffini PA;Russo R;Cristiano L;Antonosante A;d'Angelo M;Castelli V;Giordano A;Allegretti M;Cimini A
化疗诱导的周围神经病变（CIPN）是一种神经性疼痛，代表化疗药物的常见和严重后果。在过去的几年里，在阐明CIPN的潜在发病机制方面取得了重大进展。紫杉烷对微管的干扰被认为是导致轴突运输改变和永久性神经损伤的机制。化疗药物激活的炎症过程被认为是CIPN伤害性过程的潜在触发因素。在这项研究中，我们调查的影响reparixin，CXCR 1/CXCR 2的抑制剂，在抑制紫杉醇诱导的伤害性感受在大鼠的发展。此外，还分析了在逆转由紫杉醇或GRO/KC在F11细胞中诱导的神经毒性作用中的瑞帕瑞辛活性。瑞帕里辛持续输注可改善紫杉醇诱导的大鼠机械性和冷异常性疼痛。在F11细胞中，reparixin能抑制紫杉醇和GRO/KC诱导的乙酰化α-微管蛋白的增加。进行随后的实验以剖析GRO/KC控制下的信号转导途径，最终由紫杉醇和/或瑞帕霉素调节。为此目的，我们发现，瑞帕瑞辛显着抵消p-FAK，p-JAK 2/p-STAT 3，和PI 3 K-p-coronin激活诱导的紫杉醇或GRO/KC。总体而言，目前的结果已确定IL-8/CXCR 1/2途径作为参与紫杉醇诱导的周围神经病变的机制。特别是，所获得的数据表明，抑制CXCR 1/2与标准紫杉烷治疗相结合，除了增强紫杉烷抗肿瘤活性外，还可以减少化疗诱导的神经毒性，从而为开发新的治疗方法提供了一些见解。
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.