Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

Abstract

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

Increase in motility and invasiveness of MCF7 cancer cells induced by nicotine is abolished by melatonin through inhibition of ERK phosphorylation

“…While several studies demonstrate a role for nicotine in the initiation of cancer, accumulating evidence suggests that nicotine makes existing cancer more aggressive, by enhancing growth, motility, and metastasis . This is a noteworthy finding, as the use of nicotine supplements is habitually part of various smoking cessation programs.…”

“…Numerous studies have documented that melatonin displays several anticancer effects, by pleiotropically acting upon different targets, including ERK activation . Indeed, melatonin can efficiently mitigate and even suppress migration and invasiveness in different cancer types, such as nasopharyngeal, renal, gastrointestinal, and breast tumors, probably involving a wide range of different actions, including CSK remodeling …”

Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

“…The pineal hormone melatonin has demonstrated its potential usefulness in the treatment of a number of pathologies, including cancer, where it acts as an effective oncostatic agent . Previous research has shown that this indoleamine exerts antiproliferative, pro‐apoptotic, anti‐invasiveness, and anti‐angiogenic effects in HCC cell lines, and also plays a protective role in murine models of DEN‐induced hepatocarcinogenesis .…”

Melatonin attenuates osteosarcoma cell invasion by suppression of C‐C motif chemokine ligand 24 through inhibition of the c‐Jun N‐terminal kinase pathway

“…Cancer metastasis involves complex and redundant pathways that are collectively termed the invasion‐metastasis cascade; these pathways include detachment of cancer cells, motility, degradation of the extracellular matrix (ECM), invasion, migration, adhesion to endothelial cells, and re‐establishment of growth at a distant site . After epithelial‐mesenchymal transition (EMT) of cancer cells, invasion of the basement membrane proceeds through a series of discrete steps, and various matrix metalloproteinases (MMPs) predominantly control the degradation of the basement membrane .…”