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.

Melatonin induces antiproliferative activity through modulation of apoptoticpathway in H-ras oncogene transformed 5RP7 cells

“…They showed that induction of apoptosis by melatonin in prostate cancer cells (LNCaP) was observed via early/late apoptosis and caspase-3 activation. Xu et al (2013) and Martin-Renedo et al (2008) showed the apoptotic effects of melatonin in SW-1990 (pancreatic cancer) and HepG2 cells respectively by similar mechanisms. Martin-Renedo et al (2008) also showed that treatment with melatonin caused marked caspase-3 activation in HEPG2 cells (236%-362%).…”

“…et al, 1999), SK-N-MC (human neuroblastoma cell line) (Garcia-Santos et al, 2006), B65 (rat dopaminergic neuroblastoma cell line) (Pizarro et al, 2008), AR42J (rat pancreatic tumor cell line) (Uguz et al, 2012), HepG2 (hepatocarcinoma cell line) (Martin-Renedo et al, 2008;Fan et al, 2010), LnCaP (prostate cancer cell line) (Joo and Yoo, 2009), HL60 (human leukemia cell line), Jurkat (human T lymphoblastic leukemia cell line), MOLT-4 (human T lymphoblastic leukemia cell line), Daudi (human B lymphoblastic cell line), K562 (erythroleukemia cell line) (Büyükavcı et al, 2006), SNG-II (human uterine endometrial adenocarcinoma cell line), and Ishikawa (human endometrial adenocarcinoma cell line) (Kanishi et al, 2000) cell lines. Our results showed that melatonin inhibited cell viability in 5RP7 cells, and growth inhibition of the melatonin (380 µM) was both dose-and time-dependent for 24 and 48 h. However, this cytotoxic effect was not observed in the NIH/3T3 cells at this concentration.…”

“…Apoptosis resistance is one of the basic hallmarks in carcinogenesis (Sainz et al, 2003). The induction of apoptosis is significant for the development of cancer treatments (Martin-Renedo et al, 2008). Caspase-3 is a central protein in the triggering of apoptosis (Joo and Yoo, 2009).…”

Melatonin and ubiquitin: what’s the connection?

“…We have already documented the inhibitory action of melatonin on nf-κB and the role of the proteasome in activating nf-κB. Melatonin can also induce accumulation of the tumor suppressor factor p53 [101], of the stress-related enzyme JnK [102], and of the pro-apoptotic proteins Bax and caspase-3 [103] in cancer cells. It decreases the activity of the protein kinase, aKt [104], decreases the activity of the angiogenic factor, VeGf [105], and activates the transcription factor nrf-2 [106].…”

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

“…The MDM2 antagonist Nutlin-3 specifically inhibits proliferation of LNCaP cells through cell cycle arrest and apoptosis by increasing levels of p53-responsive p21 and MDM2 expressions, demonstrating that MDM2 antagonists retain functional p53 and androgen receptor signaling in human prostate cancers [4]. Melatonin, a circadian indoleamine hormone secreted by the human pineal gland, is able to directly induced cell death of several types of human tumor cells [1][2][3][4][5][6][7][8][9]. Many recent reports have shown that melatonin inhibits the growth of androgen-sensitive human LNCaP prostate cancer cells [9][10][11][12].…”