title: The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one             triggers cell apoptosis through induction of oxidative stress and upregulation             of the p38 MAPK signaling pathway in HL-60 human leukemia cells.
abstract: The aim of the present study was to discover the signaling pathways associated             with 2-(3-hydroxy-5-methoxy-phenyl)-6,7-methylenedioxyquinolin-4-one (YYK1)-induced             apoptosis in HL-60 human leukemia cells. YYK1 induced cytotoxic effects, cell             morphological changes, decreased the cell number and increased reactive oxygen             species (ROS) production and loss of mitochondrial membrane potential (ΔΨm) in             HL-60 cells. YYK1-induced apoptosis was confirmed by the terminal deoxynucleotidyl             transferase dUTP nick end labeling (TUNEL) staining. Results from colorimetric             assays and western blot analysis indicated that activities of caspase-7/-3, caspase-8             and caspase-9 were increased in YYK1-treated HL-60 cells. Western blot analysis             showed that the protein levels of extrinsic apoptotic proteins (Fas/CD95, FasL             and FADD), intrinsic related proteins (cytochrome c, Apaf-1, AIF and Endo G),             the ratio of Bax/Bcl-2 and phosphorylated p38 MAPK were increased in HL-60 cells             after YYK1 treatment. Cell apoptosis was significantly reduced after pre-treatment             with N-acetylcysteine (NAC; a ROS scavenger) or diphenyleneiodonium chloride (DPI;             a NADPH oxidase inhibitor). Blockage of p38 MAPK signaling by SB202190 abolished             YYK1-induced Fas/CD95 upregulation and apoptosis in HL-60 cells. We conclude that             YYK1 induces both of extrinsic and intrinsic apoptotic pathways via ROS-mediated             activation of p38 MAPK signaling in HL-60 human leukemia cells in vitro.
authors: Graduate Institute of Pharmaceutical Chemistry, Department of Pharmacology, China Medical University, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan, ROC.
authors: Yung-Yi
authors: YY
authors: Cheng
authors: Jai-Sing
authors: JS
authors: Yang
authors: Shih-Chang
authors: SC
authors: Tsai
authors: Chih-Chuang
authors: CC
authors: Liaw
authors: Jing-Gung
authors: JG
authors: Chung
authors: Li-Jiau
authors: LJ
authors: Huang
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Chi-Cheng
authors: CC
authors: Lu
authors: Hsi-Cheng
authors: HC
authors: Chien
authors: Minoru
authors: M
authors: Tsuzuki
authors: Sheng-Chu
authors: SC
authors: Kuo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D052117:Benzodioxoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C580924:2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one; D000970:Antineoplastic Agents; D052117:Benzodioxoles; C491901:FAS protein, human; D016166:Free Radical Scavengers; D015363:Quinolones; D017382:Reactive Oxygen Species; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D000111:Acetylcysteine