Reactive oxygen species-mitochondria pathway involved in LYG-202-induced apoptosis in human hepatocellular carcinoma HepG2 cells
Reactive oxygen species-mitochondria pathway involved in LYG-202-induced apoptosis in human hepatocellular carcinoma HepG2 cells
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DOI：
10.1016/j.canlet.2010.04.004
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发表时间：
2010-10-01
期刊：
影响因子：
9.7
通讯作者：
Guo, Qing-Long
中科院分区：
文献类型：
--
作者：
Chen, Fei-hong;Zhang, Lin-bo;Guo, Qing-Long
在此之前，我们已经证明了LYG-202是一种新合成的具有哌嗪取代的类黄酮，在体内和体外都具有明显的抗肿瘤活性。这种新化合物的确切机制尚不清楚。在本研究中，我们研究了LYG-202对人肝癌HepG2细胞凋亡过程中活性氧（ROS）产生和下游信号通路的影响。预处理ROS生成抑制剂NAC （n -乙酰半胱氨酸）可通过阻断ROS生成部分抑制LYG-202诱导的细胞凋亡。进一步的数据显示，LYG-202诱导ROS积累，随后线粒体膜电位（MMP）降低，细胞色素c （Cyt c）和凋亡诱导因子（AIF）向细胞质释放，导致细胞凋亡。此外，LYG-202还可以激活丝裂原活化蛋白激酶（MAPK），即ROS积累的下游效应，包括c-Jun n-末端激酶（JNK）和p38 MAPK。综上所述，ROS的产生可能在LYG-202诱导的线粒体凋亡途径中发挥重要作用，这进一步支持了LYG-202作为一种新的抗癌候选药物的观点。2010爱思唯尔爱尔兰有限公司版权所有。
Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen species (ROS) production and the downstream signaling pathway in the apoptosis of human hepatocellular carcinoma HepG2 cells. Pretreatment with NAC (N-acetylcysteine), a ROS production inhibitor, partly inhibited the apoptosis induced by LYG-202 via blocking the ROS generation. Further data revealed that LYG-202 induced ROS accumulation followed by a decrease in mitochondrial membrane potential (MMP), release of cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) to cytosol, which induced apoptosis of the cells. Moreover, the mitogen-activated protein kinases (MAPK), the downstream effect of ROS accumulation including c-Jun N-terminal kinase (JNK) and p38 MAPK, could be activated by LYG-202. Taken together, the generation of ROS might play an important role in LYG-202-induced mitochondrial apoptosis pathway, which provided further support for LYG-202 as a novel anticancer therapeutic candidate. (C) 2010 Elsevier Ireland Ltd. All rights reserved.