Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Poster address: 100 Haining Road Shanghai, Shanghai, 20160, China.
J Exp Clin Cancer Res. 2019 Jan 31;38(1):44. doi: 10.1186/s13046-019-1047-9.
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.
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.
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.
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.
骨肉瘤（OS）是儿童和青少年中常见的恶性肿瘤，在过去的二十年中，其治愈率没有提高。CYT997（lexibulin）是一种新型的强效微管靶向药物，在多种癌症中具有多种抗癌活性，如增殖抑制、血管破坏、细胞周期停滞和凋亡诱导。然而，CYT997 的直接细胞毒性机制尚未完全阐明。
我们评估了 CYT997 处理后人类骨肉瘤中的细胞凋亡和自噬，并研究了其潜在机制。为了探讨相互关系，我们使用了活性氧（ROS）清除剂 N-乙酰半胱氨酸（NAC）、PERK 抑制剂 GSK2606414、ERO1 抑制剂 EN460 和线粒体靶向保护肽 elamipretide。BALB/c-nu 小鼠接种 143B 肿瘤细胞，以研究 CYT997 在体内的作用。
我们探讨了 CYT997 在骨肉瘤（OS）中的体外和体内疗效和机制，并证明 CYT997 能强力抑制细胞活力并诱导细胞凋亡和自噬。CYT997 在 OS 细胞中触发活性氧（ROS）的产生，并通过内质网（ER）应激发挥致命作用。NAC 减弱了这些作用。PERK 抑制剂 GSK2606414 可阻断 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 ERO1 的激活负责诱导 ROS 产生。线粒体途径产生的 ROS 也加重 ER 应激。线粒体的保护可以减少细胞凋亡和自噬。最后，CYT997 显著减少了体内肿瘤的生长。
本研究表明，CYT997 通过触发相互增强的 ER 应激和 ROS 诱导 OS 细胞凋亡和自噬，因此可能是一种有前途的骨肉瘤治疗药物。
Zotero 插件
