Liu Chun-Yen, Hsieh Chang-Hung, Kim Seung-Hun, Wang Jing-Ping, Ni Yu-Lin, Su Chun-Li, Yao Ching-Fa, Fang Kang
Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
Int J Oncol. 2016 Dec;49(6):2431-2441. doi: 10.3892/ijo.2016.3717. Epub 2016 Oct 5.
Human liver cancer is one of the most frequently diagnosed cancers worldwide. The development of resistance to therapy limits the application against the disease. To improve treatment, new effective anticancer agents are constantly pursued. Previously, we reported that an indolylquinoline, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), is effective in suppressing the growth of human lung cancer by impairing mitochondria functions. The present study revealed that EMMQ inhibited cell growth and induced apoptosis in liver cancer cells, but not in normal cells. This study demonstrated that EMMQ induced DNA damage by activating p53 and γ-H2AX and cell arrest by suppressing cyclin D1 and CDK2. Damaged DNA injured mitochondrial functions by lowering the membrane potential and producing reactive oxygen species. The subsequent mitochondrial cytochrome c release attenuated pro-survival signals and increased apoptotic characteristics. Introduction of p53 shRNA abrogated drug effects by reducing DNA damage while maintaining mitochondria integrity. In brief, the study demonstrates that the effectiveness of EMMQ accentuated apoptosis of hepatocarcinoma cells by activating p53. Based on these collective findings, the study offered a new perspective of EMMQ that was shown to be a promising candidate to treat liver cancer.
肝癌是全球最常被诊断出的癌症之一。对治疗产生耐药性限制了其在对抗该疾病方面的应用。为了改善治疗效果，人们一直在不断寻求新的有效抗癌药物。此前，我们报道过一种吲哚基喹啉，即3-((7-乙基-1H-吲哚-3-基)-甲基)-2-甲基喹啉（EMMQ），可通过损害线粒体功能有效抑制人肺癌的生长。本研究表明，EMMQ抑制肝癌细胞的生长并诱导其凋亡，但对正常细胞无此作用。该研究证明，EMMQ通过激活p53和γ-H2AX诱导DNA损伤，并通过抑制细胞周期蛋白D1和细胞周期蛋白依赖性激酶2（CDK2）导致细胞停滞。受损的DNA通过降低膜电位和产生活性氧来损害线粒体功能。随后线粒体细胞色素c的释放减弱了促生存信号并增加了凋亡特征。引入p53短发夹RNA（shRNA）通过减少DNA损伤同时维持线粒体完整性来消除药物作用。简而言之，该研究表明EMMQ通过激活p53增强了肝癌细胞的凋亡。基于这些共同发现，该研究为EMMQ提供了一个新的视角，表明它有望成为治疗肝癌的候选药物。
