title: Cephalochromin induces G0/G1 cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by inflicting mitochondrial disruption.
abstract: The fungus-derived compound cephalochromin, isolated from the fermented broth of Cosmospora vilior YMJ89051501, shows growth-inhibitory and apoptotic activity against human lung cancer A549 cells in a concentration-dependent manner with an IC50 value of 2.8 μM at 48 h. Cephalochromin induced cell cycle arrest at the G0/G1 phase through down-regulation of cyclin D1, cyclin E, Cdk 2, and Cdk 4 expressions. Cephalochromin markedly increased the hypodiploid sub-G1 phase (apoptosis) of the cell cycle at 48 h as measured by flow cytometric analysis. Reactive oxygen species generation and loss of the mitochondrial membrane potential (MMP) were also markedly induced by cephalochromin. Moreover, the immunoblotting assays showed that cephalochromin reduced survivin and Bcl-xL expression and induced the activation of caspase-8, -9, and -3 and the cleavage of poly(ADP-ribose) polymerase, indicating the involvement of a caspase signaling cascade. The caspase inhibitor Z-VAD-fmk significantly suppressed cephalochromin-induced apoptosis. Cephalochromin also triggered LC3 II, autophagic marker, expression. Taken together, this is the first report that cephalochromin induced an antiproliferative effect on human lung cancer cells through mitochondrial disruption and down-regulation of survivin, leading to cell cycle arrest at the G0/G1 phase, loss of MMP, and subsequently apoptotic cell death.
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University , Taipei 110, Taiwan.
authors.forename: Che-Jen
authors.initials: CJ
authors.lastname: Hsiao
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chen
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Chiang
authors.forename: Li-Ya
authors.initials: LY
authors.lastname: Liu
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Tzong-Huei
authors.initials: TH
authors.lastname: Lee
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chung
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002511:Cephalosporins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016193:G1 Phase / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D002511:Cephalosporins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C011417:cephalochromin; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D020169:Caspases