Mechanisms Underlying Tumor Suppressive Properties of Melatonin

Abstract

There is considerable evidence that melatonin may be of use in the prevention and treatment of cancer. This manuscript will review some of the human, animal and cellular studies that provide evidence that melatonin has oncostatic properties. Confirmation that melatonin mitigates pathogenesis of cancer will be described from both direct study of its effects on carcinogenesis, and from indirect findings implicating disruption of the circadian cycle. A distinction is made between the role of melatonin in preventing the initiation of the tumorigenic pathway and the ability of melatonin to retard the progression of cancer. Melatonin appears to slow down the rate of advancement of established tumors and there is evidence that it constitutes a valuable complement to standard pharmacological and radiation treatment modalities. There are instances of the beneficial outcomes in cancer treatment which utilize a range of hormones and vitamins, melatonin being among the constituents of the mix. While these complex blends are empirically promising, they are only briefly mentioned here in view of the confounding influence of a multiplicity of agents studied simultaneously. The last section of this review examines the molecular mechanisms that potentially underlie the oncostatic effects of melatonin. Alterations in gene expression following activation of various transcription factors, are likely to be an important mediating event. These changes in gene activity not only relate to cancer but also to the aging process which underlies the onset of most tumors. In addition, epigenetic events such as modulation of histone acetylation and DNA methylation patterns throughout the lifespan of organisms need to be considered. The antioxidant and immunoregulatory roles of melatonin may also contribute to its cancer modulatory properties. Naturally, these mechanisms overlap and interact extensively. Nevertheless, in the interest of clarity and ease of reading, each is discussed as a separate topic section. The report ends with some general conclusions concerning the clinical value of melatonin which has been rather overlooked and understudied.

Melatonin in macrophage biology: Current understanding and future perspectives

“…Melatonin is highly pleiotropic and regulates countless physiological parameters in numerous organs. 8,[28][29][30][31] Among them, several fields deserve particular emphasis, such as the control of circadian rhythms and, in photoperiodically sensitive species, of seasonality, both in conjunction with the transmission of the signal "darkness" [32][33][34] ; modulation of differentiation and growth [35][36][37] ; antioxidative protection by various mechanisms [38][39][40][41][42] ; anti-oncogenic and oncostatic actions [43][44][45] ; and, with particular relevance to this article, immune modulation. 16,[46][47][48][49] Physiological functions of macrophages go from host defense to immune downregulation, 50,51 in addition to their homeostatic activities.…”

The emergence of melatonin in oncology: Focus on colorectal cancer

“…The relationship between melatonin and disease is apparent in: (a) affecting its endogenous melatonin levels, particularly the inhibition of the secretory nocturnal peak by excessive lighting at dark time in response to ocular signals, the so‐called “light‐at‐night idea” or LAN hypothesis of Stevens; or (b) disrupting its membrane receptor‐mediated signaling and/or receptor‐independent activities. Concomitantly, the link between circadian alterations (eg, rotating shift work or LAN), (epi)genetic changes, metabolic disorders, immune weakening, altered pattern of the human plasma proteome during circadian misalignment, and the aggravation of cancer risk is a highly discussed health issue, which consequently has generated ample epidemiologic and experimental literature . In this sense, recent additional studies have enriched the epidemiological evidence linking shift work and augmented CRC risk.…”

“…Regarding this issue, under real physiological conditions the feasibility of some of the direct effects (nonreceptor mediated) shown by melatonin have recently been questioned. In experimental systems, the verification of melatonin actions is usually carried out at concentrations higher (millimolar range) than those reached inside cells and tissues, which, according to the currently available evidence, does not exceed the picomolar/nanomolar range . Thus, it is believed that some of the direct effects reported in the clinical literature could be artifacts forced by melatonin concentrations much higher than cellular amounts and, consequently, it is suggested that most of the oncostatic mechanisms activated by physiological melatonin activity are mediated by its specific receptors.…”

Melatonin: A promising agent targeting leukemia

“…In an in vitro study, melatonin suppressed the growth of human cancer cell lines by inhibition of specific phases of cell cycles. Also, melatonin decreases metastasis and invasion by changing the expression of adhesion molecules and intracellular communication . Other oncostatin actions of melatonin in various cancers include the modulation of transactivation and expression of estrogen receptor (ERa), calcium/calmadulin and protein kinase C activity, cytoskletal structure, redox status of cells, the activity of aromatase and telomerase, and fatty acid transportation and metabolism …”

“…Also, melatonin decreases metastasis and invasion by changing the expression of adhesion molecules and intracellular communication. 68,77,78 Other oncostatin actions of melatonin in various cancers include the modulation of transactivation and expression of estrogen receptor (ERa), calcium/calmadulin and protein kinase C activity, cytoskletal structure, redox status of cells, the activity of aromatase and telomerase, and fatty acid transportation and metabolism. 70,[79][80][81][82] Besides the direct action of melatonin, this agent enables neutralizing free radicals through induction of suppression of redox enzyme activity (DUOX1&2, NOX2&4, iNOS, and mitochondria derived ROS) or antioxidant enzymes.…”