Basic Mechanisms Involved in the Anti-Cancer Effects of Melatonin

Abstract

It is commonly accepted that melatonin (N-acetyl-5-methoxytryptamine), the most relevant pineal secretory product, has oncostatic properties in a wide variety of tumors and, especially, in those identified as being hormonedependent. The objective of the present article is to offer a global and integrative view of the mechanisms involved in the oncostatic actions of this indoleamine. Due to the wide spectrum of melatonin's actions, the mechanisms that may be involved in its ability to counteract tumor growth are varied. These include: a) antioxidant effects; b) regulation of the estrogen receptor expression and transactivation; c) modulation of the enzymes involved in the local synthesis of estrogens; d) modulation of cell cycle and induction of apoptosis; e) inhibition of telomerase activity; f) inhibition of metastasis; g) prevention of circadian disruption; h) antiangiogenesis; i) epigenetic effects; j) stimulation of cell differentiation; and k) activation of the immune system. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Moreover, the list of actions described may not be exhaustive in terms of how melatonin modulates tumor growth.

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…ER α is activated by elevated intracellular cAMP levels. E2 increases cAMP, thus enhancing ER-mediated transcription [16]. The reduction of cAMP could be the mechanism underlying the decreased E2-induced ER α transcriptional activity brought about by melatonin [124].…”

“…Prolonging G1 and delaying progression to S phase is one way that melatonin drives tumor cells to become more differentiated. These data are important because aggressive tumors are associated with poor differentiation [16,17], an effect that seems to be mediated by modulation of expression of genes related to the cell cycle [18,19].…”

“…Activation of the TGFβ-1 pathway: Melatonin-dependent late apoptosis is associated with activation of the TGFβ-1 pathway, leading to increased phosphorylated mothers against decapentaplegic homolog (Smad) 2 and Smad3 levels and enabling interaction with Smad4 [16,28,66]. Smad2/Smad4 or Smad3/Smad4 complexes can thus enter the nucleus where they lead to the transcriptional induction of TGFβ-1-related genes.…”

“…The extensively studied anti-estrogenic properties of melatonin are the basis for its oncostatic actions in hormone-dependent mammary cancer [16,41] (Figure 3B). …”

“…The anti-estrogenic effects of melatonin seem to be mediated through MT 1 receptors, which are coupled to Gi proteins and inhibit adenylate cyclase activity, thus decreasing the activity of the cAMP/PKA signaling pathway [16]. ER α is activated by elevated intracellular cAMP levels.…”