title: {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic Acid Methyl Ester Inhibited Hepatocellular Carcinoma Growth in Bel-7402 Cells and Its Resistant Variants by Activation of NOX4 and SIRT3.
abstract: {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) is a novel indole compound, which possessed high efficacy against many cancers xenografted in mice without obvious toxicity. In this study, we aimed to investigate the effects of MIAM on human hepatocellular carcinoma (HCC) Bel-7402 cells and its resistant variants Bel-7402/5FU. MIAM inhibited the growth of HCC more potent in Bel-7402/5FU cells than its parent cells. MIAM increased cellular reactive oxygen species (ROS) levels, induced cell apoptosis, and arrested cell cycle in G0/G1 phase. MIAM might exert its action on Bel-7402/5FU cells through activation of NADPH oxidase 4 (NOX4)/p22(phox), Sirtuin3 (SIRT3)/SOD2, and SIRT3/p53/p21(Waf1/Cip) pathways. MIAM might inhibit HCC growth through the modulation of SIRT3. When SIRT3 was silenced, the inhibitory effect of MIAM on Bel-7402/5FU was lowered, showing the characteristic of resistance against MIAM, whereas Bel-7402/5FU cells with high expression of SIRT3 by SIRT3 adenovirus infection demonstrated the high sensitivity to MIAM. These results suggested that MIAM might exert its action against Bel-7402/5FU growth through upregulation of SIRT3. We suggested that MIAM might be a promising candidate compound which could develop as a potent anticancer agent targeting NOX4 and SIRT3 activation.
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Medical Experiments and Testing Center, Capital Medical University, Beijing 100069, China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Shiyue
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Xian-jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007210:Indoleacetic Acids / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C559930:(2-(1-(3-methoxycarbonylmethyl-1H-indol-2-yl)-1-methylethyl)-1H-indol-3-yl)acetic acid methyl ester; D000970:Antineoplastic Agents; D007210:Indoleacetic Acids; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C466093:SIRT3 protein, human; D056566:Sirtuin 3