Exosomes and platinum-induced peripheral neuropathy

摘要： 铂类药物通常用于治疗癌症。铂类药物是卵巢癌的一线治疗药物， 和结肠直肠癌。然而，化疗引起的周围神经病变（CIPN）是最常见的并发症之一。 常见并发症超过70%接受奥沙利铂治疗的患者受到神经病变的影响。 奥沙利铂诱导外周感觉神经病变的两种症状：急性和短暂性感冒加重， 和慢性形式，在多次暴露于药物后发作，并且不会随着药物的消失而消失。 停止神经毒性通常导致铂类药物剂量减少，从而影响铂类药物的疗效。 抑制肿瘤进展的药物。化疗后平均6年，47%的女性仍然 CIPN的症状。迄今为止，开发神经保护剂的研究尚未成功， 减少CIPN。迫切需要开发针对CIPN的新疗法。发展这样的挑战 治疗包括治疗不需要妨碍抗肿瘤功效，但有效抑制CIPN。我们 初步数据表明脑内皮细胞衍生的外泌体（CEC-exos）消除奥沙利铂。 在荷瘤小鼠中诱导周围神经病变并使奥沙利铂对癌细胞杀伤敏感。 外泌体是纳米囊泡，并且通过将货物蛋白、脂质和蛋白质转运到细胞内来介导细胞间通讯。 基因组材料，包括mRNA和microRNA（miRNA）之间的源和靶细胞。我们 发现用CEC-exos沿着奥沙利铂治疗荷瘤小鼠诱导了一个网络， 坐骨神经中的miRNAs/mRNAs，其在坐骨神经和DRG神经元中发挥神经保护作用，但触发 肿瘤中独特的miRNA/mRNA网络促进癌细胞死亡。因此，我们假设CEC- exos减轻铂类药物诱导的外周神经毒性，而CEC-exos增强抗- 铂类药物对肿瘤细胞的抗癌疗效。提出了三个具体的目标来测试这一整体 假说.目的1是研究CEC-exos对改善铂类药物诱导的肝细胞凋亡的作用， 周围神经毒性和提高肿瘤治疗水平。目的二是研究分子机制 CEC-exos对铂类药物诱导的周围神经病变的潜在治疗作用，重点是 CEC exosomal miRNAs与其靶蛋白在轴突和DRG神经元中的相互作用。目标3是 研究CEC-exos使肿瘤对铂类药物敏感的分子机制 重点关注CEC外泌体miRNAs与肿瘤细胞中靶蛋白的相互作用。 实现这些目标将可能导致开发一种新的CEC-exo治疗CIPN， 从而改善生活质量并可能治愈癌症。

Abstract: Platinum-based drugs are commonly used to treat cancers. Platinum drugs are the first line therapy for ovarian and colorectal cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common complications. More than 70% of the patients receiving oxaliplatin are affected by neuropathy. Oxaliplatin induces two symptoms of peripheral sensory neuropathy; an acute and transient cold-aggravated, and a chronic form that has onset after multiple exposures to the drug and does not disappear with drug cessation. The neurotoxicity often leads to platinum drug dose reductions, compromising efficiency of platinum drugs to suppress tumor progression. On an average of 6 years after chemotherapy, 47% of women still reported symptoms of CIPN. Studies to develop a neuroprotective agent have, to date, been unsuccessful to reduce CIPN. There is an imperative need to develop new therapies to CIPN. Challenges to develop such therapies include that a therapy needs not to impede antitumor efficacy, but to effectively inhibit CIPN. Our preliminary data demonstrated cerebral endothelial cell derived exosomes (CEC-exos) abolish oxaliplatin- induced peripheral neuropathy in tumor bearing mice and sensitize oxaliplatin on cancer cell killing. Exosomes are nanovesicles and mediate intercellular communication by transferring cargo proteins, lipids, and genomic materials including mRNAs and microRNAs (miRNAs) between source and target cells. We found that treatment of the tumor bearing mice with CEC-exos along with oxaliplatin induces a network of miRNAs/mRNAs in sciatic nerves that exerts neuroprotection in sciatic nerves and DRG neurons, but triggers a distinct miRNAs/mRNAs network in tumor to promote cancer cell death. We, thus, hypothesized that CEC- exos mitigate peripheral neurotoxicity induced by platinum drugs and that CEC-exos enhance the anti- cancer efficacy of platinum drugs on tumor cells. Three specific aims are proposed to test this overall hypothesis. Aim 1 is to investigate the efficacy of the CEC-exos on ameliorating platinum drug-induced peripheral neurotoxicity and on improving the treatment of tumor. Aim 2 is to investigate molecular mechanisms underlying the therapeutic effect of CEC-exos on platinum drug-induced peripheral neuropathy with a focus on the interaction between CEC exosomal miRNAs and their target proteins in axons and DRG neurons. Aim 3 is to investigate molecular mechanisms underlying the effect of CEC-exos on sensitizing tumors to platinum drugs with a focus on the interaction between CEC exosomal miRNAs and their target proteins in tumor cells. Accomplishing these aims will potentially lead to development of a new CEC-exo based therapy for CIPN, leading to improvement in the quality of life and possibly cure of cancers.