Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Cancer Lett. 2010 Oct 1;296(1):96-105. doi: 10.1016/j.canlet.2010.04.004. Epub 2010 May 23.
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 HepG(2) 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.
先前，我们证明了 LYG-202，一种新合成的带有哌嗪取代基的类黄酮，在体内和体外均表现出明显的抗肿瘤活性。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 HepG(2)细胞凋亡中活性氧（ROS）产生和下游信号通路的影响。ROS 产生抑制剂 NAC（N-乙酰半胱氨酸）的预处理部分通过阻断 ROS 的产生抑制了 LYG-202 诱导的细胞凋亡。进一步的数据表明，LYG-202 诱导 ROS 积累，随后线粒体膜电位（MMP）下降，细胞色素 c（Cyt c）和凋亡诱导因子（AIF）释放到细胞质中，从而诱导细胞凋亡。此外，MAPK（细胞外信号调节激酶），ROS 积累的下游效应包括 c-Jun N-末端激酶（JNK）和 p38 MAPK，可以被 LYG-202 激活。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，这为 LYG-202 作为一种新型抗癌治疗候选物提供了进一步的支持。
