Putting Cancer to Sleep at Night: The Neuroendocrine/Circadian Melatonin Signal

Abstract

Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. Evidence indicates that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. A new mechanism by which physiological and pharmacological blood levels of melatonin inhibit cancer growth in vivois via a melatonin-induced suppression of tumor linoleic acid (LA) uptake and its metabolism to the important mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin suppresses cAMP formation and inhibits tumor uptake of LA and its metabolism to 13-HODE via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. It has been postulated that in industrialized societies, light at night, by suppressing melatonin production, poses a new risk for the development of breast cancer and, perhaps, other cancers as well. In support of this hypothesis, light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of rat hepatoma and human breast cancer xenografts. Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth via the mechanisms described above. The nocturnal melatonin signal organizes tumor metabolism and growth within circadian time structure that can be further reinforced by appropriately timed melatonin supplementation. Dietary melatonin supplementation working in concert with the endogenous melatonin signal has the potential to be a new preventive/therapeutic strategy to optimize the host/cancer balance in favor of host survival and quality of life.

Circadian Variation of Melatonin, Light Exposure, and Diurnal Preference in Day and Night Shift Workers of Both Sexes

“…Chronic melatonin suppression has been linked to both initiation and promotion of cancer because melatonin is a hormone with oncostatic properties (4,6,36,37). However, the anticancer effects of melatonin depend on the circadian stage, as suggested by animal studies (reviewed in ref.…”

Shift work and cancer – considerations on rationale, mechanisms, and epidemiology

“…In addition to protecting DNA by suppressing the formation and accumulation of altered DNA, melatonin may also help to promote DNA repair (15,(91)(92)(93).…”

Melatonin as a Biomarker of Circadian Dysregulation

“…Growth-inhibitory and oncostatic properties of melatonin have been well described (reviewed in ref. 30). Several in vitro studies have reported a reduction in the growth of malignant cells and/or tumors of the breast (31)(32)(33)(34)(35) prostate (36)(37)(38)(39)(40)(41), and other tumor sites (42)(43)(44)(45)(46) by both pharmacologic and physiologic doses of melatonin.…”