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Melatonin: Chronobiological and Chronopharmacological Role in Cancer Prevention and Treatment
By David E. Blask, PhD, MD Dr. Blask is Senior Research Scientist in the Laboratory of Chrono-Neuroendocrine Oncology at the Bassett Research Institute, The Mary Imogene Bassett Hospital, Cooperstown, NY; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Melatonin is a fundamental, 3-4 billion-year-old indoleamine molecule found in all major non-metazoan and metazoan taxa from bacteria to man. In edible plant species, melatonin is referred to as phytomelatonin and may be considered not only a hormone, but a nutrient and/or vitamin as well.1 In humans, melatonin is a neurohormone synthesized from the amino acid tryptophan by the pineal gland, a pea-sized endocrine gland located deep within the brain. Its production and secretion into the bloodstream at night follows a circadian rhythm that is synchronized by the light/dark cycle.2 Photons of light reaching specialized photoreceptors in the eyes called retinal ganglion cells stimulate nerve impulses that are transmitted, via the retinohypothalamic tract, to the central biological clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Daylight resets the central biological clock whereas light, of sufficient intensity, wavelength, and duration, present during darkness suppresses melatonin production.3,4
During the night, melatonin secreted by the pineal gland normally reaches peak concentrations of 60-80 pg/mL between 2:00 and 3:00 a.m., whereas daytime levels are less than 10 pg/mL. The half-life of melatonin in the blood is approximately 50-60 min. It is subjected to first-pass metabolism in the liver where 90% of melatonin is catabolized to 6-sulfatoxymelatonin, which is excreted in the urine.2 The absolute oral bioavailability of melatonin (2-4 mg) is 15% with peak levels of 2-4 ng/mL being reached within approximately 1 hour of ingestion.5 The bioavailability of lower amounts (i.e., micrograms) of oral melatonin varies widely.6 Millions of people throughout the world regularly consume melatonin from commercially available nutritional supplements, primarily for sleep problems and/or jet lag.7
Melatonin, an amphiphatic molecule (possesses both a hydrophilic and hydrophobic end) that passes through all morphophysiological barriers, is involved in a wide variety of functions including circadian rhythm activity, sleep/activity cycles, body temperature, seasonal reproductive rhythms, retinal physiology, immune activity, vascular tone, intermediary metabolism, free radical / antioxidant mechanisms, mitochondrial activity, and cancer development and growth. Melatonin's mechanism of action in the regulation of many of these processes is thought to involve inhibitory G protein-coupled receptors leading to the suppression of production of the second messenger molecule, cAMP. As the biochemical expression of darkness, the circadian melatonin signal in essence "tells" the cells of the body that it is dark. In fact, the duration of nocturnal melatonin secretion indicates the length of the dark phase. In this way, melatonin acts as one of the hands of the biological clock to help coordinate physiological and metabolic activities in synchronization with the 24-hour solar day.1,2,8
Mechanisms of Melatonin's Anticancer Action
In experimental rat models of chemical carcinogenesis, both the physiological melatonin signal and the administration of exogenous melatonin just prior to the beginning of the dark phase suppress the initiation phase of tumorigenesis. One mechanism by which this may be accomplished is via melatonin's ability to suppress the accumulation of DNA adducts (the resulting complex when chemicals bind to DNA) formed by carcinogens that cause damage to and permanent alterations in DNA (i.e., mutations and amplifications), which lead to neoplastic transformation. This may be accomplished directly via melatonin's ability to act as a potent free radical scavenger and/or through its indirect actions to detoxify carcinogens via activation of the glutathione and related antioxidative pathways. In addition to protecting cells from DNA damage, it may also promote the repair of DNA once damage has occurred.9-11
In experimental models of neoplasia, melatonin, at nocturnal circulating concentrations, inhibits the proliferation of human cancer cell lines in vitro. This is achieved by delaying the progression of cells from the G1/0 to the S phase of the cell cycle. At pharmacological levels, melatonin has also been shown to exert cytotoxic effects on cancer cells in vitro. In fact, either alone or in combination with other agents, melatonin induces apoptotic cancer cell death. In some neoplastic cells, this indoleamine acts as a differentiating agent and diminishes their invasive/metastatic potential via alterations in adhesion molecule expression and the support of mechanisms responsible for gap junctional intercellular communication. Additionally, evidence in support of a variety of biochemical and molecular mechanisms of melatonin's oncostatic action has been presented, including the regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular redox status, melatonin receptor-mediated signal transduction cascades, aromatase and telomerase activity, and fatty acid transport and metabolism.9-11
An essential omega-6 polyunsaturated fatty acid (PUFA), linoleic acid (LA) is the most prevalent PUFA in the Western diet in which levels greatly exceed those required to prevent essential FA deficiency (i.e., 1% of total calories).12 As a potent promoter of both murine and human tumorigenesis, LA exerts actions on cancer cells that are diametrically opposed to many of the oncostatic actions of melatonin listed above. Its oncogenic effects, particularly on human breast cancer cells, are related to its ability to upregulate the expression of genes involved in estrogen receptor (ERα) expression, cell cycle progression, G protein signaling, and the mitogen-activated protein kinase (MAPK) growth cascade.10 In both tissue-isolated ERα (+ and ) and MCF-7 human breast cancer xenografts, melatonin acts via melatonin receptors to suppress tumor cAMP formation leading to a suppression of LA uptake and its metabolism to the mitogenic signaling molecule 13-hydroxy-octadecadenoic acid (13-HODE). Down-regulation of LA uptake and metabolism reduces the activation of the epidermal growth factor receptor (EGFR)/MAPK pathway, culminating in tumor growth inhibition.13 The fact that LA up-regulates whereas melatonin down-regulates transcriptional regulation of ERα in human breast cancer cells via a melatonin receptor-mediated inhibition of cAMP in these cells14 would potentially provide ample opportunity for cross-talk among these pathways. Like rat hepatomas, human breast cancer xenografts exhibit a circadian rhythm of tumor proliferative activity, LA uptake, and metabolism and signal transduction activity that is driven by the nocturnal, circadian melatonin signal.9-11,13
Nocturnal Melatonin Signal, Light at Night, and Human Breast Cancer Risk and Prevention
The risk of developing breast cancer is up to five times higher in industrialized nations than in underdeveloped countries. Overall, nearly 50% of breast cancers cannot be accounted for by conventional risk factors.15,16 Westernized nations have increasingly become 24-hour per day societies with greater numbers of people being exposed to more artificial light during the night both at home and particularly in the workplace.17 It has been postulated that light exposure at night may represent a unique risk factor for breast cancer in industrialized societies via its ability to suppress the nocturnal production of melatonin by the pineal gland.18 This hypothesis is based on studies showing that melatonin inhibits the development and growth of experimental models of breast cancer whereas either surgical removal of the pineal gland or exposure to constant light stimulates mammary tumorigenesis in rodents.10 This postulate is further strengthened by recent epidemiological studies demonstrating that women working night shifts have a significantly elevated risk of breast cancer presumably due to their increased exposure to light at night.19
Recent studies from our laboratory have further clarified the relationship between circadian biology, the endogenous nocturnal melatonin signal, and suppression by light at night in humans and the growth and metabolism of human breast cancer xenografts in rats. Perfusion of human breast cancer xenografts in immunodeficient, nude rats with melatonin-rich blood collected from premenopausal female subjects during the night markedly suppresses tumor proliferative activity and LA uptake, as well as 13-HODE production, as compared with melatonin-deficient blood collected during the daytime. The exposure of volunteers to bright, white light (i.e., 2800 lux at eye level) at night completely extinguishes the tumor inhibitory effects of blood collected during the night. Therefore, melatonin is the first soluble, nocturnal anticancer signal to be identified in humans that directly links the central circadian clock with some of the important mechanisms regulating breast carcinogenesis and possibly the progression of other malignancies. These findings also provide the first definitive nexus between the exposure of healthy premenopausal female human subjects to bright white light at night and the enhancement of human breast oncogenesis via disruption (i.e., suppression) of the circadian, oncostatic melatonin signal.13 The suppression of circadian melatonin production by ocular exposure to bright white light at night, leading to augmented nocturnal tumor uptake of dietary LA and its conversion to mitogenically active 13-HODE, can now be afforded serious consideration as a new risk factor for human breast cancer.11
The high nocturnal dietary intake of fat, particularly LA, reported for night shift workers20,21 coupled with melatonin suppression by exposure to light at night provide a firm mechanistic basis upon which to explain, in part, the increased risk of breast cancer in some women who work night shifts for many years.19 Thus, strategies to preserve the integrity of the circadian melatonin signal (i.e., avoidance of bright light at night, intelligent lighting design, circadian-timed physiological melatonin supplementation) coupled with modifications in nocturnal dietary fat intake may offer a unique approach to the prevention of breast cancer, and perhaps other melatonin-sensitive cancers, in our increasingly 24-hour a day society.17 This contention is further supported by recent reports in women that higher, first morning urine levels of 6-sulfatoxymelatonin22 or sleep duration ≥ 9 hours per night (longer melatonin duration?)23 are associated with a significantly decreased breast cancer risk.
Interestingly, among individuals at high risk for breast cancer, plasma melatonin concentrations are independent of the degree of risk. In cancer patients in general, the nocturnal amplitude of circulating melatonin levels has been reported to be reduced to various degrees. In breast cancer patients in particular, nocturnal circulating levels of melatonin are negatively correlated with breast cancer ERα/PgR content while tissue levels of melatonin correlate positively with tumor ERα status and negatively with the nuclear grade and proliferative index. These findings suggest that cancer cells elaborate soluble factors that negatively feedback on the mechanisms regulating nocturnal melatonin production.9,20
Over the past three decades, nearly 50 small clinical trials have been performed to test melatonin's clinical efficacy in cancer patients. Most of these trials have been performed by Lissoni and colleagues in Monza, Italy.21 In a minority of these studies, melatonin was given as a single agent while in most cases it was administered in combination with other standard therapies, including chemotherapy or radiation therapy, exclusively to patients with advanced stage solid tumors that had become refractory to standard therapy alone. More than half of these trials consisted primarily of non-randomized broad Phase II trials in which melatonin therapy was administered to patients with a wide range of malignancies; the remainder were randomized, controlled Phase II trials that were disease-specific for lung cancer, colorectal cancer, breast cancer, glioblastoma, and brain metastases from solid tumors. In no case were the trials double-blind and/or placebo-controlled. An oral dose of anywhere from 10 mg to 50 mg of melatonin (usually 20 mg) was administered to cancer patients in the early evening either alone or concurrently with chemo- or radiation therapy. Although an objective partial tumor response was observed in a small percentage of patients receiving melatonin, the majority of tumor responses consisted of disease stabilization. Probably the most dramatic effect of melatonin treatment was a markedly improved one-year survival in these patients compared with those receiving supportive care, chemotherapy, or radiotherapy alone.9,20,21,24,25
Other benefits that accrue from melatonin therapy as reported in Lissoni's studies are a reduction in the toxicities associated with chemotherapy including myelotoxicity, nephrotoxicity, thrombocytopenia, lymphocytopenia, stomatitis, neuropathy, and cancer cachexia. Probably the most clinically important aspect of these trials is that melatonin-treated cancer patients apparently achieve and maintain better performance status and experience less anxiety than those individuals not receiving the indoleamine. Performance status represents the results of subjective assessment of the amount and timing of daytime and nighttime activity and daytime and nighttime rest or sleep. In fact, patients who have a better performance status at the outset usually respond more favorably to melatonin alone or in combination with other more conventional therapies. Performance status has been shown repeatedly to be predictive of survival, quality of life, and response to a variety of therapeutic approaches including surgery, chemotherapy, hormonal therapy, and radiation.20,21,24,25
Safety and Toxicity
The most common adverse effect of therapeutic (milligram) doses of melatonin include sedation, drowsiness, and mild hypothermia. Other side effects, though infrequent, include altered sleep patterns, fatigue, headache, increased seizure activity in neurologically impaired pediatric patients, confusion, pruritis, and dysphoria.26 In a recent randomized, double-blind, placebo-controlled trial, oral melatonin (10 mg) administered prior to sleep for one month was found to exert no toxic effects on a wide range of physiological and neurological parameters.27 In the Lissoni clinical cancer trials, in which up to 50 mg of melatonin was administered daily for 1-3 years, no adverse side effects warranting its discontinuation were reported.21
The nocturnal, circadian melatonin signal is a newly identified inhibitory link between the central circadian pacemaker in the brain and the processes governing cancer development and growth in both experimental animals and humans. This anticancer signal in essence organizes the processes controlling oncogenesis within biological time structure and in doing so, provides the body with a degree of protection from the development and growth of cancer cells during each night. Melatonin blocks the ability of cancer cells to take-up LA and convert it to the mitogenic signaling molecule 13-HODE. Bright light at night, which suppresses this oncostatic signal, represents a newly identified risk factor for breast cancer in night-shift workers. Clinical trials indicate that nighttime melatonin supplementation may offer a promising new approach in the treatment of advanced stage malignancies and reduction in the toxicity of chemotherapy and/or radiation. Pharmacological doses of melatonin appear to be safe and generally well tolerated. It is premature at this time to conclude whether melatonin will ultimately be regarded as a mainline cancer treatment strategy or alternative therapy.
Although existing clinical data on the use of melatonin as a single agent for the treatment of a wide variety of malignancies appear promising, they are not definitive enough to make a general recommendation for its use as a single-agent, first-line therapy. On the other hand, melatonin administration could be considered by oncologists as an adjunct to chemo- and/or radiotherapeutic approaches, particularly in advanced malignancies that have become refractory to these standard first-line treatments. Although animal studies suggest a role for melatonin in the chemoprevention of cancer, large-scale human prevention trials will be required before a general recommendation can be offered in this area. Nevertheless, strategies to preserve the integrity of the endogenous, circadian melatonin signal (i.e., avoidance of bright light at night, intelligent lighting design, circadian-timed physiological melatonin supplementation) coupled with modifications in nocturnal dietary fat intake may ultimately offer a unique approach to the prevention and treatment of melatonin-sensitive cancers.
Research performed by the author and his colleagues and cited in this article was generously supported by PHS Grants R01CA76197, R01CA85408 from the National Cancer Institute, the Laura Evans Memorial Breast Cancer Research Award of the Edwin W. Pauley Foundation, the Stephen C. Clark Foundation, and the Louis Busch Hager Cancer Center Research Support Grant.
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