Melatonin is an important natural oncostatic agent. At present there are no data available as to its possible influence on tumor angiogenesis, which is a major biological mechanism responsible for tumor growth and dissemination. It is well known that vascular endothelial growth factor (VEGF) is crucial to a solid tumor's higher vascularization and development. To investigate the possible influence of melatonin on angiogenesis, we studied the effect of melatonin on endogenous VEGF expression in three human cancer cell lines (PANC-1, HeLa and A549 cells). In this study, we report that physiologic concentrations of melatonin have no obvious impact on the VEGF expression, whereas pharmacologic concentrations of melatonin suppress the VEGF mRNA and protein levels induced by hypoxia mimetic cobalt chloride (CoCl(2)). Melatonin also decreases hypoxia-inducible factor (HIF)-1alpha protein levels, suggesting a role for transcription factor HIF-1 in the suppression of VEGF expression. The effect of pharmacologic concentrations of melatonin on VEGF and HIF-1alpha under normoxia is uncertain, which indicates that the regulatory mechanisms of VEGF in the absence or presence of CoCl(2) are different and other or additional transcription factors may be involved. Taken together, our data show that melatonin in high concentrations markedly reduces the expression of endogenous VEGF and HIF-1alpha induced by CoCl(2) in cultured cancer cells.

Melatonin, an indolamine mainly produced in the pineal gland, has received a great deal of attention in the last decade because of its oncostatic effects, which are due to its immunomodulatory, antiproliferative, antioxidant and its possible antiangiogenesis properties. Herein, we document its antiproliferative action on human umbilical vein endothelial cells (HUVECs). Moreover, the possible cell signaling pathways when melatonin inhibited HUVEC proliferation were explored in this study. Primary HUVECs were isolated, cultured, purified and identified before the studies were performed. HUVECs were found to possess G-protein-coupled membrane receptors for melatonin (MT1 and MT2) and also nuclear melatonin receptors (RORalpha and RORbeta, especially RORbeta). No obvious expression of RORgamma was found. We investigated the membrane receptors and several intracellular signaling pathways including mitogen-activated protein kinases (MAPK)/extracellular signal-related kinases (ERK), phosphoinositol-3-kinase (PI3K)/Akt and protein kinases C (PKC) involved in antiproliferative action of melatonin on HUVECs. The blockade of these pathways using special inhibitors decreased cell growth. Furthermore, the constitutive activation of nuclear factor kappa B (NF-kappaB) contributed to the proliferation of HUVECs. High concentrations of melatonin inhibited both NF-kappaB expression and its binding ability to DNA, possibly through inactivation of ERK/Akt /PKC pathways. Taken together, high concentrations of melatonin markedly reduced HUVEC proliferation; the antiproliferative action of melatonin was closely correlated with following pathway: melatonin receptors/ERK/PI3K/Akt/PKC/ NF-kappaB.

Melatonin is the major secretory product of the pineal gland and is considered an important natural oncostatic agent. The anticancer activity of melatonin is due to its immunomodulatory, anti-proliferative and antioxidative effects. At present there are no direct data available as to melatonin's possible influence on angiogenesis, which is a major biological mechanism responsible for tumor growth and dissemination. The current study investigated the influence of melatonin on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were cultured, identified, and purified. Cell growth and viability, DNA fragmentation and cell cycle analyses were determined. To elucidate the mechanism of action of melatonin, Western blot analyses for P53, Bax and Bcl-2 expression were carried out. The results demonstrate the anti-proliferative and apoptosis-inducing effects of melatonin; these changes were associated with cell cycle arrest, upregulation of P53 and Bax and downregulation of Bcl-2. Taken together, our data showed that melatonin in high concentrations markedly reduces HUVECs proliferation, induces cellular apoptosis, and modulates cell cycle length. P53 and Bax/Bcl-2 expression changes may be involved in these actions of melatonin.