title: Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line.
abstract: Melatonin reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in the treatment of hepatocarcinoma are limited. In this study, we examined the effect of melatonin administration on HepG2 human hepatocarcinoma cells, analyzing cell cycle arrest, apoptosis and mitogen-activated protein kinase (MAPK) signalling pathways. Melatonin was dissolved in the cell culture media in 0.2% dimethyl sulfoxide and administered at different concentrations for 2, 4, 6, 8 and 10 days. Melatonin at concentrations 1000-10,000 microM caused a dose- and time-dependent reduction in cell number. Furthermore, melatonin treatment induced apoptosis with increased caspase-3 activity and poly(ADP-ribose) polymerase proteolysis. Proapoptotic effects of melatonin were related to cytosolic cytochrome c release, upregulation of Bax and induction of caspase-9 activity. Melatonin treatment also resulted in increased caspase-8 activity, although no significant change was observed in Fas-L expression. In addition, JNK 1,-2 and -3 and p38, members of the MAPK family, were upregulated by melatonin treatment. Growth inhibition by melatonin altered the percentage or cells in G0-G1 and G2/M phases indicating cell cycle arrest in the G2/M phase. The reduced cell proliferation and alterations of cell cycle were coincident with a significant increase in the expression of p53 and p21 proteins. These novel findings show that melatonin, by inducing cell death and cell cycle arrest, might be useful as adjuvant in hepatocarcinoma therapy.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institute of Biomedicine, University of León, León, Spain. jgonga@unileon.es
authors.forename: Javier
authors.initials: J
authors.lastname: Martín-Renedo
authors.forename: José L
authors.initials: JL
authors.lastname: Mauriz
authors.forename: Francisco
authors.initials: F
authors.lastname: Jorquera
authors.forename: Olga
authors.initials: O
authors.lastname: Ruiz-Andrés
authors.forename: Paquita
authors.initials: P
authors.lastname: González
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C022616:thiazolyl blue; D008550:Melatonin