Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Cancer Lett. 2016 Nov 28;382(2):157-165. doi: 10.1016/j.canlet.2016.08.028. Epub 2016 Sep 6.
Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines. In addition, Riluzole induced caspase-dependent apoptosis and G2/M cell cycle arrest in SNU449 and Huh7 cell lines. In a line with the known function of glutamate release inhibitor, we found Riluzole-treated cells have increased the level of inner cellular glutamate that in turn decrease the glutathione (GSH) level and finally augment the reactive oxygen species (ROS) production. We confirm this finding in vivo by showing the Riluzole-induced GSH and ROS changes in a Huh7 xenograft cancer model. Altogether, these data suggest the anti-cancer effect of Riluzole on hepatocellular carcinoma and the suppression of glutamate signaling might be a new target pathway for HCC therapy.
肝癌是许多国家常见的恶性肿瘤之一，也是癌症死亡的一个日益增加的原因。尽管如此，可用的治疗选择很少，且结果不一致，这就需要开发替代的治疗选择。通过药物重新定位筛选，我们发现并研究了利鲁唑（一种肌萎缩侧索硬化症（ALS）药物）在肝癌（HCC）治疗中的作用机制。利鲁唑的治疗导致肝原代癌细胞和癌细胞系的细胞增殖受到抑制。此外，利鲁唑诱导 SNU449 和 Huh7 细胞系中 caspase 依赖性细胞凋亡和 G2/M 细胞周期停滞。根据谷氨酸释放抑制剂的已知功能，我们发现利鲁唑处理的细胞内谷氨酸水平升高，进而降低谷胱甘肽（GSH）水平，最终增加活性氧（ROS）的产生。我们通过显示利鲁唑在 Huh7 异种移植癌症模型中诱导的 GSH 和 ROS 变化，在体内证实了这一发现。总之，这些数据表明利鲁唑对肝癌具有抗癌作用，抑制谷氨酸信号可能是 HCC 治疗的新靶点途径。
