title: A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity.
abstract: We previously reported that 7-hydroxy-5, 4'-dimethoxy-2-arylbenzofuran (HDAB) purified from Livistona chinensis is a key active agent. The present study investigated the function and molecular mechanism of HDAB. HDAB treatment of cervical cancer cells resulted in S phase arrest and apoptosis, together with cyclin A2 and CDK2 upregulation. Cyclin A2 siRNA and a CDK inhibitor efficiently relieved S phase arrest but increased the apoptosis rate. Mechanistic studies revealed that HDAB treatment significantly increased DNA strand breaks in an alkaline comet assay and induced ATM, CHK1, CHK2 and H2A.X phosphorylation. Wortmannin (a broad inhibitor of PIKKs) and CGK733 (a specific ATM inhibitor), but not LY294002 (a phosphatidylinositol 3-kinase inhibitor) or NU7026 (a DNA-PK specific inhibitor), prevented H2A.X phosphorylation and γH2A.X-positive foci formation in the nuclei, reversed S phase arrest and promoted the HDAB-induced apoptosis, suggesting that HDAB is a DNA damaging agent that can activate the ATM-dependent DNA repair response, thereby contributing to cell cycle arrest. In addition, molecular docking and in vitro activity assays revealed that HDAB can correctly dock into the hydrophobic pocket of PARP-1 and suppress PARP-1 ADP-ribosylation activity. Thus, the results indicated that HDAB can function as an anti-cancer agent by inducing DNA damage and inhibiting PARP activity.
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1] The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Zhanjiang 524023, Guangdong, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.affiliation: Clinical laboratory, Zhuhai People's hospital, Zhuhai 519000, China.
authors.forename: Pinghong
authors.initials: P
authors.lastname: Ming
authors.affiliation: Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
authors.forename: Caiping
authors.initials: C
authors.lastname: Guo
authors.affiliation: Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Drug Discovery and Design Center (DDDC), Shanghai Institute of Materia Medica, Shanghai 201203, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
authors.forename: Xiangjiu
authors.initials: X
authors.lastname: He
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, and Division of Life and Health Sciences, Tsinghua University Shenzhen Graduate School, Shenzhen 518055, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D056751:Cyclin A2; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051357:Cyclin-Dependent Kinase 2