Melatonin: A double-edged sword for cancer treatment

Melatonin is an endogenous indolamine produced in the pineal gland. As main secretory product, melatonin has many effects on a wide range of physiological functions, including regulation of circadian rhythms; acting as an immunomodulatory agent and its role as a free radical scavenger and antioxidant. Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system’s ability to readily detoxify the reactive intermediates or to repair the resulting damage. Numerous studies have reported on the way that melatonin acts as a potent antioxidant. Melatonin is 5 and 14 times more effective at scavenging the toxic hydroxyl radical than glutathione and mannitol respectively. Furthermore, melatonin has been shown to potently neutralize such ROS as hydrogen peroxide, peroxynitrite anion, the peroxyl radical and HClO. The wide spectrum of the melatonin antioxidant activity also includes an indirect effect by up-regulating several antioxidant enzymes. Studies reveal that melatonin increases the activity of antioxidant enzymes like as glutathione peroxidase, glutathione reductase, glucose-6- phosphate dehydrogenase, catalase and peroxide dismutase. This hormone also increases the effect of other antioxidants, such as glutathione and E and C vitamins. Based on its antioxidant function, several in vitro and in vivo studies have widely demonstrated the antiproliferative effect of melatonin in many types of tumors, for example breast cancer and glioma. However, recent works revealed that melatonin also has cytotoxic effects on specific tumors. With this dual action, it seems like oxidative stress plays a key role. The cytotoxic effects of melatonin primarily have been demonstrated in Ewing Sarcoma Family of Tumors (ESFT), hematological malignancies, colorectal cancer and biliary cancer. These studies reached the same conclusions: the cytotoxic effect of melatonin is induced using pharmacological concentrations of the indolamine (1 mM); it is mediated by apoptosis mechanisms and melatonin stimulates the production of free radicals. In ESFT and hematological malignancies, the role of the extrinsic apoptotic pathway in melatonin’s effect is established predominantly by the activation of FasR and FasL. The triggering of the intrinsic pathway has been also shown, although this activation seems to be mediated by the link between the two pathways, Bid. In these apoptotic signaling pathways, oxidative stress exerts a double effect: the early increase in free radicals cooperates with this signaling pathway, in contrast, the later increase is consequence of the cell death process. This increase in free radicals due to melatonin’s effect is overcome by antioxidants, also preventing melatonin’s cytotoxic effect, demonstrating the key role of oxidative stress. Apart from melatonin’s effect alone, its combination with other chemotherapeutic drugs induces a synergistic effect, strengthening the extrinsic apoptotic signaling pathway as well as increasing oxidative stress. Furthermore, numerous studies suggest that melatonin could benefit cancer patients since it enhances the immune system, protects against free radicals and guards the body from the harmful effects of chemotherapy. These studies suggest that melatonin could be taken into account as a drug with uses for cancer treatment in combination with the current chemotherapeutic drugs, reducing the dose of these agents and the toxicity for the patient.