Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Abstract

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

Melatonin alleviates the heat stress‐induced impairment of Sertoli cells by reprogramming glucose metabolism

“…Previous studies have shown that melatonin promotes glucose uptake but reduces lactic acid production in murine SCs 32 . Many cancer‐related studies have also found that melatonin inhibits the aerobic glycolysis (Warburg effect), PPP, and TCA cycles of tumor cells and induces apoptosis 44–46 . Why are the phenomena that we observe distinct from theirs?…”

“…32 Many cancer-related studies have also found that melatonin inhibits the aerobic glycolysis (Warburg effect), PPP, and TCA cycles of tumor cells and induces apoptosis. [44][45][46] Why are the phenomena that F I G U R E 6 Melatonin and heat stress have opposite regulation of the TCA cycle in SCs. (A) Effect of heat stress or melatonin on characteristic genes indicative of TCA cycle and OXPHPS was shown by GSEA analysis.…”

Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma

“…Previous research indicated that the melatonergic system is mainly involved in circadian rhythms, but recent studies also revealed its role in anti-inflammatory, antidepressant, antioxidant, and antitumor activities. The melatonergic system has been found to exert anticancer efficacy through activating apoptosis, regulating cell proliferation signaling, modulating survival signals, and inhibiting angiogenesis [ 10 ]. Furthermore, melatonin inhibits the transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis by regulating key enzymes and glucose transporters.…”

Histological Effect of Gemcitabine on the Liver and Kidney of Male Rat with and without Melatonin

“…Gemcitabine is detoxified in the liver to the active diphosphate and triphosphate nucleosides by the aid of nucleoside kinase enzyme [4]. This drug cannot differentiate between normal cell and malignant cell, so it produces its toxic effect on both cells but the normal cells can repair the injury and retain their normal function while the malignant cell will be destructed and all the adverse reactions of gemcitabine are due to this process [5]. As all other anticancer agents, it may cause gastrointestinal upset including nausea, vomiting, and constipation, in addition to other side effects such as hair loss, bone marrow suppression, and fertility complications [6].…”