Cancer metastasis: Mechanisms of inhibition by melatonin

Abstract

Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and nonneoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell-cell and cell-matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial-mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases. K E Y W O R D Sangiogenesis, epithelial-mesenchymal transition, matrix metalloproteinase, melatonin, metastasis

Rubus idaeusInhibits Migration and Invasion of Human Nasopharyngeal Carcinoma Cells by Suppression of MMP-2 through Modulation of the ERK1/2 Pathway

“…The proteolytic events of the metastasis process involve various proteases, such as serine proteinase, plasminogen activator, cathepsin and matrix metalloproteinases (MMPs) (Cheng et al, 2016;Su et al, 2016;Yeh et al, 2016;Su et al, 2017). MMPs are a family of zinc-dependent endopeptidases that are collectively capable of degrading most components of the basement membrane and ECM, and increased expressions of these enzymes are detected in almost all human cancers and have been associated with the aggressiveness of various neoplasms (Cox et al, 2001;Shuman Moss et al, 2012).…”

“…45, No. 7, 1557-1572© 2017 down-regulating the ERK1/2 signaling pathway, suggesting that Rubus idaeus may serve as chemotherapeutic and chemopreventive agent for NPC. …”

Oral Mucositis: Melatonin Gel an Effective New Treatment

“…Melatonin gel treatment in the mouth, which was observed to reduce intestinal morpho-pathological changes [17], is therefore also associated with improved preservation of both small intestinal and oral mucosa. have also been reported in numerous studies [116][117][118]. Given its capacity to increase the efficacy of anticancer drugs, these data show that melatonin can be used not only to treat mucositis due to the absence of adverse side effects, but also can be used in cancer co-treatment programs.…”

“…Additionally, melatonin has an important metabolic effect, which decreases glucose uptake by cancer cells [114] and inhibits tumor growth through the suppression of the uptake of linoleic acid and its metabolism by the tumor to the mitogenic molecule 13-HODE [115]. Its anti-angiogenic and anti-metastatic properties have also been reported in numerous studies [116][117][118]. Given its capacity to increase the efficacy of anticancer drugs, these data show that melatonin can be used not only to treat mucositis due to the absence of adverse side effects, but also can be used in cancer co-treatment programs.…”

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats

“…These data provide clues for understanding new mechanisms related to melatonin-mediated inhibition of angiogenesis in OC, and might aid in uncovering novel combination therapies to control tumor growth. Recently, a number of mechanisms underlying melatonin's effects on the levels of HIF-1α and VEGF have been discussed, such as via its antioxidant capacity [23,54], functional alteration of the ubiquitin ligase, von Hippel-Lindau (VHL) protein [55], changes in particular microRNA, and others [56]. While some hypotheses have been provided, the mechanisms regulating shifts in the balance of angiogenic activators and regulators remain inconclusive for OC.…”