Oral melatonin supplementation in rats and a human subject suppresses the growth activity of steroid receptor negative human breast cancer xenografts in female nude rats via an MT1 receptor-mediated suppression of signal tranduction and linoleic acid uptake and metabolism
Authors: David E. Blask, Robert T. Dauchy, Leonard A. Sauer, Leslie K. Davidson, Jean A. Krause, Darin T. Lynch, Erin M. Dauchy
Journal: Cancer Research (2005)

5776  The nocturnal circadian production of melatonin by the pineal gland provides an anticancer signal to tissue-isolated rat hepatoma 7288CTC. Melatonin’s anticancer mechanism involves a melatonin receptor-mediated reduction in cAMP formation resulting in an inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE); 13-HODE up-regulates the activity of the epidermal growth factor receptor/ MEK/ ERK1/2 growth pathway. Very little is known about melatonin’s anticancer effects on human breast cancer growth in vivo. We tested the effects of oral melatonin supplementation in both rats and a human subject on signal transduction activity, LA uptake/metabolism and growth activity in tissue-isolated, steroid receptor (SR) negative MCF-7 human breast cancer xenografts in female nude rats. These rats are nocturnally active and consume 90% of their food and water during the dark phase of a light/dark cycle (lights on 0600 - 1800 hrs). In study 1, beginning 2 wks prior to tumor implantation and continuing until the end of the study, groups of rats were given free access to drinking water to which melatonin and/or melatonin receptor antagonists were added. Rats consumed melatonin (5 μg/day) and receptor antagonists (10 μg/day), S20928 (MT1 receptors; Servier) or 4P-PDOT (MT2 receptors), either alone or in combination with melatonin. Tumor xenografts completely failed to develop in rats ingesting melatonin, either alone or in combination with 4P-PDOT. In contrast, melatonin suppression of tumor growth was completely blocked by S20928. Tumor growth activity, LA uptake, 13-HODE formation and cAMP levels were significantly higher in rats ingesting S20928, either alone or in combination with melatonin, than in controls; neither MEK nor ERK1/2 activation was affected. In study 2, (SR-) human breast cancer xenografts were perfused in situ for 1 hr with donor whole-blood collected during midday from an adult human volunteer just before and 1 hr after the oral ingestion of a commercial melatonin supplement (3 mg). Following oral melatonin intake, serum melatonin levels were increased by 75-fold and perfusion of tumors with melatonin-rich whole-blood resulted in a 70% decrease in tumor [3H]thymidine incorporation into DNA, and near total suppression of tumor cAMP levels, LA uptake/13-HODE formation, and MEK/ERK1/2 activation. These are the first results to demonstrate that oral melatonin supplementation, in rats and a human subject, prevented the proliferative activity of tissue-isolated (SR-) human breast cancer xenografts via a suppression of tumor signal transduction activity and LA uptake/13-HODE formation exclusively through an MT1 melatonin receptor-mediated mechanism.