title: 3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells.
abstract: In the present study, we evaluated 3-Hydroxyter-phenyllin (3-HT) as a potential anticancer agent using the human ovarian cancer cells A2780/CP70 and OVCAR-3, and normal human epithelial ovarian cells IOSE-364 as an in vitro model. 3-HT suppressed proliferation and caused cytotoxicity against A2780/CP70 and OVCAR-3 cells, while it exhibited lower cytotoxicity in IOSE-364 cells. Subsequently, we found that 3-HT induced S phase arrest and apoptosis in a dose-independent manner. Further investigation revealed that S phase arrest was related with DNA damage which mediated the ATM/p53/Chk2 pathway. Downregulation of cyclin D1, cyclin A2, cyclin E1, CDK2, CDK4 and Cdc25C, and the upregulation of Cdc25A and cyclin B1 led to the accumulation of cells in S phase. The apoptotic effect was confirmed by Hoechst 33342 staining, depolarization of mitochondrial membrane potential and activation of cleaved caspase-3 and PARP1. Additional results revealed both intrinsic and extrinsic apoptotic pathways were involved. The intrinsic apoptotic pathway was activated through decreasing the protein levels of Bcl2, Bcl-xL and procaspase-9 and increasing the protein level of Puma. The induction of DR5 and DR4 indicated that the extrinsic apoptotic pathway was also activated. Induction of ROS and activation of ERK were observed in ovarian cancer cells. We therefore concluded that 3-HT possessed anti-proliferative effect on A2780/CP70 and OVCAR-3 cells, induced S phase arrest and caused apoptosis. Taken together, we propose that 3-HT shows promise as a therapeutic candidate for treating ovarian cancer.
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Compton
authors.affiliation: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Rankin
authors.affiliation: Department of BioMolecular Sciences, University of Mississippi, University, MS 38677, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Youying
authors.initials: Y
authors.lastname: Tu
authors.affiliation: College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA.
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001230:Aspergillus / Q000737:chemistry*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010053:Ovary / Q000166:cytology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015398:Signal Transduction; D013730:Terphenyl Compounds / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D013730:Terphenyl Compounds; D016159:Tumor Suppressor Protein p53; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C020624:3-hydroxyterphenyllin