title: 3,5-Dimethyl-H-furo[3,2-g]chromen-7-one as a potential anticancer drug by inducing p53-dependent apoptosis in human hepatoma HepG2 cells.
abstract: OBJECTIVE
  Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives.
  
  
  METHODS
  Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity.
  
  
  RESULTS
  Among the 6 derivatives, 3,5-dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC(50) value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl.
  
  
  CONCLUSIONS
  DMFC is potentially an effective therapeutic agent in liver cancer therapy.
authors: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Zhejiang University, Hangzhou, PR China.
authors: Jian-guo
authors: JG
authors: Sun
authors: Chao-yue
authors: CY
authors: Chen
authors: Ke-wang
authors: KW
authors: Luo
authors: Chi-lam Au
authors: CL
authors: Yeung
authors: Tsun-yee
authors: TY
authors: Tsang
authors: Zhi-zhen
authors: ZZ
authors: Huang
authors: Ping
authors: P
authors: Wu
authors: Kwok-pui
authors: KP
authors: Fung
authors: Tim-tak
authors: TT
authors: Kwok
authors: Fei-yan
authors: FY
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
chemical_list: C560573:3,5-dimethyl-7H-furo(3,2-g)chromen-7-one; C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C494811:BCL2L1 protein, human; D001572:Benzofurans; D003374:Coumarins; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D019014:fas Receptor; D045304:Cytochromes c; D020169:Caspases