CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma
CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma
复制标题
CYT997(Lexibulin) 通过激活骨肉瘤中相互增强的 ER 应激和 ROS 诱导细胞凋亡和自噬
DOI：
10.1186/s13046-019-1047-9
复制
发表时间：
2019-01-31
影响因子：
11.3
通讯作者：
Cai, Zhengdong
中科院分区：
文献类型：
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作者：
Wang, Zongyi;Yin, Fei;Cai, Zhengdong
背景：骨肉瘤（OS）是儿童和青少年常见的恶性肿瘤，其治愈率在过去二十年中没有提高。CYT 997（lexibulin）是一种新型的有效的微管靶向剂，具有多种抗癌活性，如增殖抑制、血管破坏、细胞周期阻滞和诱导凋亡，在多种癌症中。然而，CYT 997的直接细胞毒性机制尚未完全characterized.Methods：我们评估了细胞凋亡和自噬与CYT 997治疗后的人骨肉瘤，并探讨了潜在的机制。为了探索关系，我们使用了活性氧（ROS）清除剂N-乙酰半胱氨酸（NAC），PERK抑制剂GSK 2606414，ERO 1抑制剂EN 460和线粒体靶向保护肽elamipretide。结果：CYT 997对骨肉瘤（osteosarcoma，OS）的体内、外治疗效果及作用机制研究表明，CYT 997能有效抑制OS细胞的生长，诱导OS细胞凋亡和自噬。CYT 997通过内质网（ER）应激触发OS细胞中ROS的产生并发挥致死作用。NAC减弱了这些影响。PERK抑制剂GSK 2606414可以阻断ER应激途径，减少ROS产生并增强细胞活力。此外，ER应激途径中的ERO 1的激活负责诱导ROS产生。由线粒体途径产生的ROS也加重ER应激。保护线粒体可以减少细胞凋亡和自噬。最后，CYT 997显着降低肿瘤生长在vivo.Conclusions：这项研究表明，CYT 997诱导OS细胞凋亡和自噬，通过触发相互增强的ER应力和ROS，因此可能是一个有前途的代理对OS。
Background:Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized.Methods:We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997.Results:We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo.Conclusions:This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS.