Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD.
Ann Neurol. 2013 Dec;74(6):893-904. doi: 10.1002/ana.24004.
Peripheral neurotoxicity is a major dose-limiting side effect of many chemotherapeutic drugs. Currently there are no effective disease-modifying therapies for chemotherapy-induced peripheral neuropathies, but these side effects of chemotherapy are potentially ideal targets for development of neuroprotective therapies, because candidate drugs can be co- or preadministered before the injury to peripheral axons takes place.
We used a phenotypic drug screening approach to identify ethoxyquin as a potential neuroprotective drug and carried out additional biochemical experiments to identify its mechanism of action.
We validated the screening results with ethoxyquin and its derivatives and showed that they prevented paclitaxel-induced peripheral neuropathy without blocking paclitaxel's ability to kill tumor cells. Furthermore, we demonstrated that ethoxyquin acts by modulating the chaperone activity of heat shock protein 90 (Hsp90) and blocking the binding of 2 of its client proteins, ataxin-2 and Sf3b2. Ethoxyquin-induced reduction in levels of both of these proteins resulted in prevention of axonal degeneration caused by paclitaxel.
Ethoxyquin and its novel derivatives as well as other classes of small molecules that act as Hsp90 modulators may offer a new opportunity for development of drugs to prevent chemotherapy-induced axonal degeneration.
周围神经毒性是许多化疗药物的主要剂量限制副作用。目前，尚无针对化疗引起的周围神经病的有效疾病修饰疗法，但这些化疗的副作用是开发神经保护疗法的潜在理想靶点，因为候选药物可以在周围轴突损伤发生之前共同或预先给药。
我们使用表型药物筛选方法鉴定乙氧喹啉作为一种潜在的神经保护药物，并进行了额外的生化实验来确定其作用机制。
我们用乙氧喹啉及其衍生物验证了筛选结果，表明它们可以预防紫杉醇引起的周围神经病，而不会阻止紫杉醇杀死肿瘤细胞的能力。此外，我们证明乙氧喹啉通过调节热休克蛋白 90（Hsp90）的伴侣活性并阻止其 2 个客户蛋白，ataxin-2 和 Sf3b2 的结合来发挥作用。乙氧喹啉诱导的这两种蛋白水平降低导致紫杉醇引起的轴突退化得到预防。
乙氧喹啉及其新型衍生物以及其他作为 Hsp90 调节剂的小分子类别可能为开发预防化疗引起的轴突退化的药物提供新的机会。
