In 1992, the Life Extension Foundation introduced a melatonin supplement because of the broad-spectrum protective effects that this hormone had shown against age-related disease.1 Some of this research even suggested that melatonin supplementation may extend the human life span.2 Indeed, melatonin is so intricately involved in cell regulatory processes that scientists are now studying it as an adjunctive cancer treatment.3,4
These days, most people are likely to associate melatonin with a hormone that helps people sleep better or prevents jet lag.5,6 Few people realize that melatonin is a cancer-killing hormone7,8 that can enhance the human immune system,9,10 protect against the toxic side effects of chemotherapy4,11 and radiation therapy,12,13 and improve wound healing after cancer surgery.14,15 Even fewer are aware of ongoing clinical trials in which melatonin is being used to help cancer patients better manage their disease symptoms,16 improve their quality of life,17 and even increase their survival rates.4,11
Although the evidence demonstrating melatonin’s anti-cancer effects18 cannot be overstated, melatonin’s impact on cancer treatment remains largely unappreciated. This is likely because pharmaceutical companies have little to gain by advertising the anticancer efficacy of melatonin. In Europe, where melatonin is not even readily available, many clinical trials of melatonin have been conducted.19,20 US pharmaceutical companies, however, have shown little interest in even hosting, let alone funding, such critically important and potentially lifesaving clinical trials.
Life Extension Supports Clinical Trial
The Life Extension Foundation is collaborating with Cancer Treatment Centers of America on the first prospective, randomized clinical trial utilizing melatonin in patients with advanced lung cancer. Life Extension is providing, at no charge, high-dose melatonin and placebo supplements for this ongoing clinical trial, which will be the first in the US to examine the effect of melatonin supplementation therapy on quality of life and overall survival rates for patients with metastatic non-small-cell lung cancer.
Figure 1. Structure of Melatonin (C13H16N2O2)
Life Extension and the Cancer Treatment Centers of America hope to determine whether patients with advanced lung cancer suffer abnormal circadian rhythms and whether this affects their melatonin levels. The researchers hope that this trial will confirm the favorable clinical results documented by Lissoni and colleagues, whose recent European clinical studies indicate that in patients with metastatic non-small-cell lung cancer, five-year survival and overall tumor regression rates were higher in patients concomitantly treated with melatonin than in those treated with chemotherapy alone.4 While no patient treated with chemotherapy survived after two years, five-year survival was achieved in 3 of 49 patients treated with chemotherapy and melatonin. The researchers hope that similarly promising results could eventually convince mainstream medical practitioners to administer melatonin in combination with standard cancer treatment regimens to patients in earlier stages of cancer treatment.
Numerous, mostly European clinical studies already have examined melatonin’s therapeutic benefits to patients with different types of cancer who either did not respond to standard oncological therapies11,19 or were eligible only for supportive care (advanced cancer deemed untreatable by conventional standards).21,22 A literature search of the PubMed database found 806 publications on “melatonin and cancer.” Fifty-two articles were found concerning clinical studies utilizing melatonin in cancer patients. In this article, we will highlight and summarize some of the key studies concerning the use and mechanisms of melatonin as an adjuvant cancer therapy.
What Is Melatonin?
Melatonin (known scientifically as the indoleamine N-acetyl-5-methoxytryptamine) is a hormone with neurotransmitter modulatory activity.23 It is produced from the amino acid tryptophan in minute quantities by the pineal gland when the eyes detect no light (i.e., in darkness or blindness, or during sleep). Melatonin also is produced by the retina24 and, in vastly greater amounts, by the gastrointestinal system.25 In fact, 400 times more melatonin can be found in the gastrointestinal system than in the pineal gland or bloodstream,26 where levels typically range from 0.1 to 10 nmol/L. Melatonin receptors are present in central nervous tissues,27 peripheral tissues,28 and steroidogenic tissues,29 including myometrial tissues of both pregnant and non-pregnant women.SPAN class=wwwMagTextRefNumber>30 Maternal melatonin crosses the placenta.31
Melatonin levels peak during the night but also increase after eating,26 which partly explains why one may feel sleepy after a meal and why patients with advanced cancer who suffer diminished appetite or tissue wasting have been shown to have reduced levels of melatonin.32-34 Once produced, melatonin remains in the bloodstream only a short time, on average between 20 and 90 minutes.23,35 This is because melatonin is highly fat soluble (lipophilic) and somewhat water soluble (hydrophilic), enabling it to easily penetrate every cellular compartment (membrane, cytoplasm, and nucleus) and, as far as is known, every cell in the body.36 Melatonin’s amphiphilicity, or ability to both absorb and repel water—in conjunction with its ability to act as a weak preventive antioxidant,37 a weak metal ion chelator,38 and in certain circumstances, a direct free radical scavenger39—enables it to counteract oxidative stress within the chaotic tumor microenvironment.40
Melatonin’s Anti-Cancer Mechanisms
Melatonin can kill directly many different types of human tumor cells.3,41 It is a naturally produced cytotoxin, which can induce tumor cell death (apoptosis).7,42 In instances where the tumor has already established itself in the body, melatonin has been shown to inhibit the tumor’s growth rate.43,44 Melatonin exhibits natural oncostatic activity and inhibits cancer cell growth.45 In patients in whom cancer already has become a noticeable physical burden and produces overt symptoms, melatonin has been shown to alleviate numerous cancer symptoms46 and to inhibit development of new tumor blood vessels (tumor angiogenesis),47 which in turn inhibits the cancer from spreading further (metastasis).48 Melatonin can retard tumor metabolism and development by lowering the body temperature;35 it is a natural inducer of hypothermia. Furthermore, as an inducer of antioxidants49 and itself a weak preventive antioxidant,37 melatonin hinders tumor cells from participating in free radical damage to normal cells and consequently limits oxidative damage to DNA,40 lipids,50 amino acids, and proteins.40
In the unfortunate circumstance in which cancer has already overwhelmed the body’s innate cancer-fighting capabilities, including the anti-cancer activity of naturally produced melatonin (levels of which are reduced in most cancer patients), supplemental melatonin may be beneficial.17,43 Melatonin plays a critical role in the host defense system against cancer’s progression by activating the cytokine system,51 which exerts growth-inhibiting properties,10 and by stimulating the cytotoxic activity of macrophages and monocytes.52
Administration of supplemental melatonin has been shown to be beneficial even in the supportive care of advanced and end-stage cancer patients: it lessens tissue wasting and diminishes weight loss, fatigue, weakness, and depression;17,21,43,47,53 enhances immune function;10 improves wound healing;54 and improves quality of life and survival rates.4 Furthermore, melatonin improves common symptoms found in both patients with advanced cancer and those undergoing chemotherapy; it counteracts anemia55 and lymphocytopenia,14,21 stimulates platelet production,21 enhances appetite,16 and diminishes cancer pain56 (including bone pain) through its natural analgesic properties.57 These are substantial benefits considering that approximately half of all patients diagnosed with cancer die because of poor symptom management.58