Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.

Keywords: cholangiocarcinoma; hepatocellular carcinoma; liver cancer; melatonin.

Figure 1

Flow diagram of the search and study selection performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. WOS, Web Of Science.

Figure 2

Temporal distribution of the number of articles published after 2004 which evaluate melatonin effects in liver tumors with only in vitro or in vivo models, with both type of models or in a case report.

Figure 3

Cellular processes and protein expression modulated by melatonin in liver tumors. CAT, catalase; CDK, cyclin-dependent kinase; cIAP, cellular inhibitor apoptotic proteins; COX-2, cyclooxygenase-2; ERCC1, DNA excision repair cross complementary 1 protein; ERK, extracellular signal-regulated kinase; FOXA2, forkhead box A2; FoxO3a, forkhead box protein O3; foxp3, forkhead box P3; GPx, glutathione peroxidase; GSH, reduced glutathione; GST, glutathione S-transferase; HIF-1α, hypoxia-inducible factor 1α; IL-1, interleukin-1; IL-1β, interleukin 1 beta; IL-6, interleukin-6; IL-10, interleukin-10; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase 1; LC3, microtubule-associated protein 1 light chain 3; lncRNA, long non-coding RNA; MEK, MAPK/ERK kinase 1; MMP-9, matrix metalloproteinase 9; Mn-SOD, manganese superoxide dismutase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; Nrf2, nuclear erythroid 2-related factor 2; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; PD-L1, programmed death ligand 1; PINK1, PTEN induced putative kinase 1; RAF-1, ras activated factor 1; ROS, reactive oxygen species; Sirt3, sirtuin 3; Snail, zinc finger protein SNAI1; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances; TGF-β, transforming growth factor β; Th17, IL-17-producing T helper; TIMP-1, tissue inhibitor of metalloproteinases 1; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; XIAP, cellular and X-linked inhibitor apoptotic proteins.