HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.
HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.
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DOI：
10.1097/j.pain.0000000000000893
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发表时间：
2017-06
期刊：
影响因子：
7.4
通讯作者：
Kavelaars A
中科院分区：
文献类型：
--
作者：
Krukowski K;Ma J;Golonzhka O;Laumet GO;Gutti T;van Duzer JH;Mazitschek R;Jarpe MB;Heijnen CJ;Kavelaars A
化疗引起的周围神经病变是癌症治疗最常见的剂量限制性副作用之一。目前，没有食品和药物管理局批准的治疗方法。组蛋白脱乙酰酶6（HDAC 6）是微管相关的脱乙酰酶，其功能包括调节α-微管蛋白依赖性细胞内线粒体转运。在这里，我们研究了HDAC 6抑制对已建立的顺铂诱导的周围神经病变的影响。我们使用了一种新的HDAC 6抑制剂ACY-1083，其对HDAC 6的选择性是其他HDAC的260倍。我们的研究结果表明，HDAC 6抑制预防顺铂诱导的机械异常性疼痛，也完全逆转了已经存在的顺铂诱导的机械异常性疼痛，自发性疼痛和麻木。这些发现得到了HDAC 6抑制剂ACY-1215（Ricolinostat）的证实，该药物目前正在进行癌症治疗的临床试验。在机制上，用HDAC 6抑制剂处理增加了外周神经中的α-微管蛋白乙酰化。此外，HDAC 6抑制恢复了顺铂诱导的胫神经中线粒体生物能学和线粒体含量的降低，表明线粒体转运增加。在稍后的时间点，背根神经节线粒体生物能量学也得到改善。HDAC 6抑制恢复了顺铂治疗小鼠表皮内神经纤维密度的损失。我们的研究结果表明，HDAC 6的药理学抑制完全逆转了所有的特点，建立顺铂诱导的周围神经病变的正常化线粒体功能的背根神经节和神经，和恢复表皮内神经支配。这些结果特别有希望，因为这里测试的HDAC 6抑制剂之一目前正在临床试验中作为附加癌症治疗，突出了我们研究结果快速临床转化的潜力。
Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration–approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of a-tubulin–dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatininduced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased a-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatininduced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.