title: An indolylquinoline derivative activates DNA damage response and apoptosis in human hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Seung-Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Ni
authors.affiliation: Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Su
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Ching-Fa
authors.initials: CF
authors.lastname: Yao
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
authors.forename: Kang
authors.initials: K
authors.lastname: Fang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D011798:Quinaldines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000617120:3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline; C530104:CCND1 protein, human; C468783:H2AX protein, human; D006657:Histones; D007211:Indoles; D011798:Quinaldines; D011804:Quinolines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D045304:Cytochromes c; C037073:2-methylquinoline; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2