Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

Abstract

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.

Keywords: apoptosis; cancer; melatonin; mitochondria; reactive oxygen species.

Figure 1

Melatonin induces ROS production in cancer cells through calmodulin binding. Melatonin binds to calmodulin, leading to the release of sequestered Ca²⁺-independent PLA2, which is then free to move to membranes and to release high doses of AA; in turn, liberated AA feeds 5-LOX to produce free radicals. Melatonin (aMT); Ca²⁺-independent PLA2 (iPLA2); arachidonic acid (AA); 5-lipoxygenase (5-LOX). Image created using BioRender.com(accessed on 16 July 2022).

Figure 2

Different mechanisms by which melatonin induces ROS production in cancer cells. Melatonin inhibits the AKT pathway, leading to the activation of GSK-3β, which induces NRF2 degradation. On the other hand, melatonin regulates Sirtuin 3 (SIRT3) through its activation or inhibition, leading to an anti-Warburg effect or SOD inhibition, respectively. Finally, melatonin has been shown to inhibit SIRT1 in cancer cells. All these processes lead to an increase in ROS production and antitumor activity. Melatonin (aMT); glycogen synthase kinase-3β (GSK-3β); superoxide dismutase (SOD); pyruvate dehydrogenase (PDH). Image created using BioRender.com (accessed on 18 July 2022).

Figure 3

Possible mechanisms of action of melatonin to induce ROS production via RET. In our view, melatonin increases mitochondrial CII activity, membrane potential, and CoQH2/CoQ, leading to RET-ROS production. Image created using BioRender.com (accessed on 22 July 2022).