Mitochondrial trafficking as a protective mechanism against chemotherapy drug-induced peripheral neuropathy: Identifying the key site of action
Mitochondrial trafficking as a protective mechanism against chemotherapy drug-induced peripheral neuropathy: Identifying the key site of action
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DOI：
10.1016/j.lfs.2023.122219
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发表时间：
2023-11-08
期刊：
影响因子：
6.1
通讯作者：
Yang，In Hong
中科院分区：
文献类型：
--
作者：
Albin，Bayne;Qubbaj，Khayzaran;Yang，In Hong
目的化疗所致的周围神经病变(CIPN)是一种常见的副作用，可见于接受过大多数化疗的患者，但目前尚无治疗方法。CIPN已被证明可导致轴突变性导致周围神经病变(PN)，这可以导致主要剂量的减少，并可能阻止进一步的化疗，因为经常使人虚弱的疼痛。在此之前，我们已经确定了微管靶向剂紫杉醇(PTX)的位置特异性作用，以及氟喹诺酮(FA)对紫杉醇诱导的周围神经病变(PIPN)的神经保护作用。主要方法对所有样本进行线粒体转运分析，其中FA显示顺行(轴突)线粒体转运增强，导致对所有样本的神经保护作用。关键发现利用该系统，我们证明PTX、甲基金黄色E(MMAE)和长春新碱(VCR)在局部治疗轴突时，在临床规定的水平上是毒性的。然而，顺铂(CDDP)被确定为对细胞体具有更高的毒性。尽管有不同的靶向机制，FA的给药被确定为对所有接受测试的化疗药物具有显著的神经保护作用。意义本研究确定了关于作用部位和神经保护策略的关键见解，以进一步开发作为治疗CIPN的潜在药物。FA与每种化疗药物一起治疗，以确定对CIPN的神经保护作用，在CIPN中，FA被发现对所有测试的药物具有神经保护作用。这项研究发现，FA治疗导致了基于荧光成像的线粒体顺行运动的增强。
AimsChemotherapy induced peripheral neuropathy (CIPN) is a common side effect seen in patients who have undergone most chemotherapy treatments to which there are currently no treatment methods. CIPN has been shown to cause axonal degeneration leading to Peripheral Neuropathy (PN), which can lead to major dosage reduction and may prevent further chemotherapy treatment due to oftentimes debilitating pain. Previously, we have determined the site-specific action of Paclitaxel (PTX), a microtubule targeting agent, as well as the neuroprotective effect of Fluocinolone Acetonide (FA) against Paclitaxel Induced Peripheral Neuropathy (PIPN).Main methodsMitochondrial trafficking analysis was determined for all sample sets, wherein FA showed enhanced anterograde (axonal) mitochondrial trafficking leading to neuroprotective effects for all samples.Key findingsUsing this system, we demonstrate that PTX, Monomethyl auristatin E (MMAE), and Vincristine (VCR), are toxic at clinically prescribed levels when treated focally to axons. However, Cisplatin (CDDP) was determined to have a higher toxicity when treated to cell bodies. Although having different targeting mechanisms, the administration of FA was determined to have a significant neuroprotective effect for against all chemotherapy drugs tested.SignificanceThis study identifies key insights regarding site of action and neuroprotective strategies to further development as potential therapeutics against CIPN. FA was treated alongside each chemotherapy drug to identify the neuroprotective effect against CIPN, where FA was found to be neuroprotective for all drugs tested. This study found that treatment with FA led to an enhancement in the anterograde movement of mitochondria based on fluorescent imaging.