Melatonin and Hormonal Therapy
Melatonin levels in cancer patients have been correlated with tumor aggressiveness and progression.90,91 A high percentage of women with estrogen-receptor-positive breast cancer have low plasma melatonin levels.92 Conversely, melatonin inhibits human breast cancer cell growth45 and reduces tumor spread and invasiveness in vitro.48 Indeed, it has been suggested that melatonin acts as a naturally occurring anti-estrogen on tumor cells, as it down-regulates hormones responsible for the growth of hormone-dependent mammary tumors.93
Melatonin differs from the classic anti-estrogens such as tamoxifen in that it does not seem to bind to the estrogen receptor or interfere with the binding of estradiol to its receptor.94 Moreover, melatonin can increase the therapeutic efficacy of tamoxifen95 and biological therapies such as IL-2.96 How melatonin interferes with estrogen signaling is unknown, though recent studies suggest that it acts through a cyclic adenosine monophosphate (cAMP)-independent signaling pathway.93 It has been proposed that melatonin suppresses the epidermal growth factor receptor3 and exerts its anti-proliferative effects by inducing differentiation97 as proposed for melanoma cells.98
Regardless of the mechanism, in tumorigenesis studies melatonin reduced the incidence and growth rate of breast tumors and slowed breast cancer development.99 Furthermore, prolonged oral melatonin administration significantly reduced the development of existing mammary tumors in animals.100 In a metastatic hormone-refractory prostate cancer patient, oral melatonin (5 mg/day) induced disease stabilization for six weeks.44
While the optimal dose of melatonin for treating different types of cancer has not yet been established, the many clinical studies by Lissoni and colleagues have shown that doses of 10-50 mg of melatonin nightly are beneficial to cancer patients.
Those recently diagnosed with slow-growing or early-stage cancer may wish to consider supplementing with 3 to 6 mg melatonin nightly; the latter dose may be reserved for early-stage cancer patients who suffer from disturbed sleep patterns. Because most clinical studies have shown that patients with late-stage, advanced, or untreatable cancer, or those with cancer metastasis, benefit from supplementation with 20 mg of melatonin, such patients may wish to consider supplementing with between 6 and 50 mg of melatonin nightly, depending on plasma melatonin levels.
Physicians should be strongly encouraged to prescribe substitutional melatonin therapy to cancer patients with depressed melatonin levels.
Night Light, Melatonin, Meditation, and Cancer Incidence
Low levels of melatonin have been associated with breast cancer occurrence and development. Women who work predominantly at night and are exposed to light, which inhibits melatonin production and alters the circadian rhythm, have an increased risk of breast cancer development.101 In contrast, higher melatonin levels have been found in blind and visually impaired people, along with correspondingly lower incidences of cancer compared to those with normal vision, thus suggesting a role for melatonin in the reduction of cancer incidence.102
Light at night, regardless of duration or intensity, inhibits melatonin secretion and phase-shifts the circadian clock, possibly altering the cell growth rate that is regulated by the circadian rhythm.103 Disruption of circadian rhythm is commonly observed among cancer patients104,105 and contributes to cancer development and tumor progression.106 Cancer alters neuroendocrine system function in such a way that melatonin levels are lower in patients with non-small-cell lung cancer.107 Indeed, the circadian rhythm of melatonin is also altered in advanced gastrointestinal malignancies, such as colorectal, gastric, and pancreatic cancer, with respect to healthy humans.108
Deregulation of many circadian clock functions in the human body—including blood pressure, temperature, hormones, sleep-wake pattern, immune function, and digestive activity—has been used as an independent prognostic factor of survival time and tumor response for patients with certain metastatic cancers.109 The circadian rhythm alone is a statistically significant predictor of survival time for breast cancer patients.110
Several studies have shown that the circadian clock is involved in tumor suppression at the systemic, cellular, and molecular levels, and that cancer should no longer be treated as a local disorder. For instance, the circadian clock regulates the immune response. Disruption of circadian rhythms could therefore lead to immunosuppression, which could disrupt cancer cell immunosurveillance and promote tumor development; however, melatonin as a circadian mediator can target the endogenous clock86 and has been shown to inhibit immunosuppression.111
The phenomenon of light at night regulating melatonin levels may explain the spontaneous tumor regression reported to occur through meditation alone in cancer patients (when the eyes are closed and detect no light).112-114 The regular practice of meditation is associated with increased physiological levels of melatonin.115,116
Pharmacological doses of supplemental melatonin can resynchronize individuals shown to have disrupted circadian rhythms,36,117 such as night-shift workers.118 Thus, cancer patients with endogenously depressed melatonin levels may benefit from both meditation and substitutional melatonin therapy, to improve quality of life119 while potentially inhibiting tumor growth and spread.
Melatonin and Advanced Cancer
Numerous clinical studies by Lissoni and colleagues have shown that melatonin adjuvant therapy favorably influences the course of advanced cancer, leading to an improved quality of life and increased survival.17,21 In cancer patients with untreatable advanced solid tumors, melatonin significantly lowered the frequency of catabolic wasting (cachexia), weakness (asthenia), low platelet (thrombocytopenia), and white blood cell counts (lymphocytopenia) compared to patients who received supportive care only. Melatonin improved disease stabilization and increased survival percentages at one and five years.4,21
Melatonin deficiencies in advanced cancer patients may be due to altered circadian rhythm (disturbed sleep patterns), cancer-related anorexia-cachexia, and reduced food intake as melatonin is produced by the enterochromaffin cells in the gastrointestinal tract in response to feeding.25 Melatonin supplementation in turn increases appetite,26 diminishes tissue wasting,21,46 and restores sleep continuity in those with cancer.5,71,120 Administration of melatonin to patients with advanced cancer who have only short expected survival times results in some cases in disease stabilization and improvement of performance status.17,43,119
Melatonin Supplementation and Cancer
Extrapolating the reduced melatonin levels observed in aging humans121,122 to the cellular level, one might expect to find less melatonin at the cellular level in tumors32,107 compared to normal healthy cells if tumor cells “age” (because of their increased growth rate) more rapidly than normal healthy cells. The potentially lower melatonin levels in tumor cells could possibly be normalized by melatonin supplementation, which in turn would be expected to lead to a negative growth advantage in the tumor microenvironment and therefore inhibit tumor growth. Melatonin levels are depressed in individuals with cancers of different origins during the phase of primary tumor growth,110 whereas normal melatonin levels may be found when remission occurs.123