Melatonin as a Repurposed Drug for Melanoma Treatment

Abstract

Melanoma is the most aggressive type of skin cancer, with a greater risk of metastasis and a higher prevalence and mortality rate. This cancer type has been demonstrated to develop resistance to the known treatment options such as conventional therapeutic agents and targeted therapy that are currently being used as the standard of care. Drug repurposing has been explored as a potential alternative treatment strategy against disease pathophysiologies, including melanoma. To that end, multiple studies have suggested that melatonin produced by the pineal gland possesses anti-proliferative and oncostatic effects in experimental melanoma models. The anticarcinogenic activity of melatonin is attributed to its ability to target a variety of oncogenic signaling pathways, including the MAPK pathways which are involved in regulating the behavior of cancer cells, including cell survival and proliferation. Additionally, preclinical studies have demonstrated that melatonin in combination with chemotherapeutic agents exerts synergistic effects against melanoma. The goal of this review is to highlight the mechanistic insights of melatonin as a monotherapy or combinational therapy for melanoma treatment.

Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells

“…Furthermore, regulation of their endogenous production/metabolism can serve as a rational strategy for targeted therapies of melanoma patients. Thus, based on results presented here and hypothesized recently Kleszczy ński and Böhm [91] and others [92,93], we are tempted to claim that melatonin, and also its metabolites, may boost commonly used BRAF/MEK inhibitors; however, these investigations still need to be carefully checked using in vitro and in vivo models.…”

Melatonin: A Potential Regulator of DNA Methylation

“…In light of the recent findings that melatonin combined with conventional anti-cancer therapy could limit the adverse effect of chemotherapy and increase its therapeutic efficacy, including reducing drug resistance [ 159 , 160 , 161 , 162 , 166 , 167 ], its simultaneous use with DNMT inhibitors or other epigenetic drugs may be a more efficient approach to avoid the limitations of epigenetic drugs. A growing number of clinical trials has investigated the plausible favorable effects of therapies when anticancer drugs are combined with DNMT inhibitors.…”

“…However, the currently used DNMT inhibitors have limitations (an inconsistent demethylation response and high toxicity level during prolonged use), which can be potentially overcome by using combined anti-cancer therapies. Accordingly, melatonin has beneficial effects when it is combined with chemotherapy [ 159 , 160 , 161 , 162 , 166 , 167 ], and it can regulate the expression of DNMT [ 84 ] or TET [ 87 , 89 ]. Therefore, it may also be more efficient when it is added to epigenetic therapy.…”

Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review

“…Increasing evidence suggests that melatonin ( N -acetyl-5-methoxytryptamine) is a cell protector endowed with systemic effects against many types of cancer [ 12 , 13 , 14 , 15 , 16 ], including breast cancer [ 17 , 18 , 19 , 20 ]. In this regard, melatonin possesses antioxidant properties, which may help to protect cells from damage caused by free radicals and other harmful substances that can contribute to cancer development [ 21 ].…”