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.
This study compared the effects of melatonin supplementation on markers of oxidative stress, and on the activity and expression of antioxidant enzymes in the liver of young (3-month-old) and aging (24-month-old) rats. Animals were supplemented with melatonin in the drinking water (20 mg/L) for 4 wk. Liver concentration of thiobarbituric-reactive substances (TBARS), as an index of lipid peroxidation, and the oxidized to reduced glutathione ratio significantly increased in aged rats (+58%), while values did not significantly differ from the young in aged animals receiving melatonin. Significant decreases in the liver activities of Cu,Zn-superoxide dismutase (SOD) (-25%), cytosolic (-21%) and mitochondrial (-40%) glutathione peroxidase (GPx), and catalase (CAT) (-34%) were found in aged rats. Melatonin abolished these changes and also prevented the reduction of Cu,Zn-SOD (-33%), cytosolic GPx (-30%), and mitochondrial GPx (-47%) liver protein content as measured by Western blot. Reductions in Cu,Zn-SOD mRNA (-39%), and GPx mRNA (-86%) levels induced by aging were also abolished by melatonin. In summary, our data indicate that melatonin treatment abrogates oxidative stress in the liver of aged rats, and that prevention of the decreased activity of CAT and the downregulation of Cu,Zn-SOD and GPx gene expression contribute to this effect.
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