Differential anti-proliferative effects of melatonin in prostate cancer cells versus normal prostate cells: Involvement of senescence and cell cycle as dual mode of action. Free

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In the United States, prostate cancer (PCa) continues to be the most common non-skin cancer, the second leading cause of death from cancer among men, and the seventh leading cause of death in this country. The number of new cases of PCa, now estimated at more than 230,000 per year, is expected to increase to >380,000 by 2025 because of the aging male population. Chemoprevention by non-toxic agents represents a promising approach to reducing the morbidity and mortality of PCa. In this study, we determined the anti-proliferative effects of melatonin, (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, against PCa and the mechanism of its biological effects. Employing androgen responsive prostate carcinoma LNCaP, androgen unresponsive prostate carcinoma PC-3 and DU145 cells, normal human prostate epithelial (PrEC) cells, and normal human prostate stromal (PrSC) cells, we determined the antiproliferative effects of melatonin (10 nM - 2 mM for 24 - 72 hours) against PCa. Our data demonstrated that melatonin treatment to PCa cells, only at higher concentrations (>1 mM), resulted in a significant i) decrease in the viability and growth of cells, ii) a G1 phase cell cycle arrest, and iii) decrease in colony formation ability of the cells. Notably, melatonin, even at the highest concentration (2 mM), was not found to have any effects of the growth or viability of the normal PrEC and PrSC cells. Interestingly, the low concentrations of melatonin (10 nM - 100 μM for 72 hours) resulted in an induction of senescence as assessed by histochemical detection of beta-galactosidase activity. Further, the melatonin-mediated increase in senescence-associated beta-galactosidase staining was found to be accompanied with a significant increase in the protein levels of maspin and 15-lipoxygenase-2 (15-LOX-2), known markers of senescence. Thus, our data suggested that melatonin may impart antiproliferative/chemopreventive effects against PCa without affecting the normal prostate cells. Further, melatonin has a dual mode of action i.e. senescence (at lower concentrations) and cell cycle blockade/cell growth inhibition (at higher concentrations). Based on these studies, we suggest that melatonin could be developed as an agent for the management of prostate cancer. However, the molecular mechanism(s) of the biological effect of melatonin and its potential in appropriate animal models remains to be elucidated; and such studies are currently ongoing in our laboratory.