title: DMFC (3,5-dimethyl-7H-furo[3,2-g]chromen-7-one) regulates Bim to trigger Bax and Bak activation to suppress drug-resistant human hepatoma.
abstract: 3,5-Dimethyl-7H-furo[3,2-g]chromen-7-one (DMFC) is a coumarin derivative with anti-cancer activity against human hepatoma cells, but the mechanisms underlying DMFC function in cancer suppression is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying DMFC anti-cancer activity and determining whether DMFC is effective in suppression of drug-resistant human hepatocellular carcinoma. We show here that DMFC effectively suppresses both the parent and the multidrug-resistant hepatoma cell growth in vitro and DMFC suppresses hepatoma cell growth at least in part through inducing tumor cell apoptosis. In the molecular level, we observed that DMFC treatment decreases Bcl-2 level by a post-transcriptional mechanism and activates Bim transcription to increase Bim mRNA and protein level in hepatoma cells. Furthermore, co-immunoprecipitation studies revealed that DMFC-induced Bim interrupts interactions between Bcl-2 and Bax and between Mcl-1 and Bak, resulting in dissociation of Bax from Bcl-2 and Bak from Mcl-1 and subsequent activation of both Bax and Bak. Activation of Bax and Bak leads to mitochondrial outer membrane permeabilization and cytochrome c release. Consistent with its potent apoptosis-inducing activity, DMFC exhibited potent activity against the multidrug-resistant hepatoma xenograft growth in vivo. Therefore, we determine that DMFC suppresses hepatoma growth through decreasing Bcl-2 and increasing Bim to induce tumor cell apoptosis and hold great promise for further development as a therapeutic agent to treat chemoresistant hepatoma.
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.|Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.|Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Zhejiang University Hospital, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.|Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.|Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
authors.affiliation: Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China.|School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People's Republic of China.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China. liuf64@zju.edu.cn.|Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People's Republic of China. liuf64@zju.edu.cn.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C560573:3,5-dimethyl-7H-furo(3,2-g)chromen-7-one; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; D000072224:Bcl-2-Like Protein 11; D001572:Benzofurans; D003374:Coumarins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: 3,5-Dimethyl-7H-furo[3,2-g]chromen-7-one, DMFC; Apoptosis; Bim; Drug-resistance; Hepatocellular carcinoma