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.

During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well funded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn's disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.

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:  In this article, we review the experimental data supporting an oncostatic role of melatonin on hormone‐dependent mammary tumors. Beginning with the evidence on the role of estrogens in breast cancer etiology and mammary tumor growth, we summarize the actual therapeutic strategies with estrogens as a target. Additionally, we demonstrate that melatonin fulfills all the requirements to be considered as an antiestrogenic drug which shares properties with drugs of the two main pharmacological groups of substances which interact with the estrogen‐signaling pathways such as: (i) drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens; and (ii) drugs that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors. Furthermore, melatonin decreases circulating levels of estradiol. These three antiestrogenic mechanisms suggest that melatonin may have an important role in the prevention and treatment of hormone‐dependent mammary cancer.

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Most of the current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. However, a possible effect of melatonin on the local synthesis of estrogens had not been examined. The objective of this work was to study whether melatonin may modify the aromatase activity in MCF-7 breast cancer cells thus modulating the local estrogen biosynthesis. In MCF-7 cells cultured with testosterone in estradiol-free media, melatonin (1 nM) counteracts the testosterone-induced cell proliferation dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. We found that melatonin reduces the aromatase activity (measured by the tritiated water release assay) of MCF-7 cells both at basal conditions and when aromatase activity was stimulated by cAMP or cortisol. The greatest inhibition of the aromatase activity was obtained with 1 nm melatonin, the same concentration that gives the highest antiproliferative and anti-invasive effects of MCF-7 cells. Finally, by RT-PCR, we found that melatonin downregulates aromatase expression at the transcriptional level in the MCF-7 cells. We conclude that melatonin, at physiological concentrations, decreases aromatase activity and expression in MCF-7 cells. This aromatase inhibitory effect of melatonin, together with its already known antiestrogenic properties interacting with the estrogen-receptor, makes this indoleamine an interesting tool to be considered in the prevention and treatment of hormone-dependent mammary neoplasias.

Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence.In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness; this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and β 1 -integrin.The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERα and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer.