Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.

中文翻译：

---

紫杉醇诱导的周围神经病变的发病机制：使用啮齿动物和人类模型系统进行的体外和体内研究结果的最新综述。


紫杉醇（商品名紫杉醇）广泛用于治疗乳腺癌、卵巢癌和肺癌等常见癌症。尽管紫杉醇在阻止肿瘤进展方面非常有效，但它也会导致 60-70% 化疗患者出现周围神经病变。许多实验室最近的努力旨在确定紫杉醇诱导的周围神经病（PIPN）的潜在机制。使用啮齿动物背根神经节神经元、人类诱导多能干细胞和啮齿动物体内模型的体外模型揭示了感觉神经元轴突和其他细胞类型（例如免疫系统和外周神经胶质细胞）内紫杉醇影响的许多分子途径，还有皮肤。这些研究表明，紫杉醇会诱导钙信号传导改变、神经肽和生长因子释放、线粒体损伤和活性氧形成，并可以激活介导细胞外信号反应的离子通道。最近的研究还表明基质金属蛋白酶 13 (MMP-13) 在介导神经病变中发挥作用。这些不同的变化可能是紫杉醇诱导的微管运输损伤继发的。人类遗传学研究虽然仍然有限，但也强调了 PIPN 中细胞骨架变化的参与。这些研究产生的新发现的分子靶标可以为开发预防或逆转化疗患者紫杉醇诱导的周围神经病变的疗法提供基础。