2047

Recent data suggest that resveratrol, a stilbene in red wine, may be a natural anti-angiogenic compound (Anticancer Res. 26:1237 2006). Angiogenesis is a complex process regulated by numerous activators and inhibitors. Hypoxia inducible factor-1α (HIF1α) is stabilized in hypoxic cancer cells and upregulates several proangiogenic factors such as vascular endothelial growth factor (VEGF) and has been associated with aggressive cancer and poor prognosis in cancer. VEGF stimulates vascular endothelial cells to move toward and eventually into a tumor while protecting them from death during migration. VEGF expression is associated with poorer survival, increased malignancy and metastasis, and is shown to promote angiogenesis. Thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, counterbalances the endothelial cell effects of VEGF in the body. TSP1 binds to endothelial cell CD36 receptors, activating apoptotic signalling pathways. The balance between VEGF and TSP1 can influence neo-vascularization in a patient’s tumor. The tumor suppressor gene p53 has been shown to modulate angiogenesis by up-regulating transcription of numerous anti-angiogenic factors, including TSP1. We previously established a relationship between p53, TSP1, and angiogenesis in clinical tumor specimens of breast, melanoma, ovary, and prostate (Cancer Detect Prev 22:185 1998, Clin Cancer Res 11:3733 2005, Clin Cancer Res 7:81 2001). Our data further demonstrated that the presence of mutant p53 correlated with the loss of wild-type (wt) p53 function manifest by decreased TSP1 expression, and increased angiogenesis; patients with lower TSP-1 had shorter survival. Thus, agents that upregulate intratumoral TSP1 may be of clinical benefit. Here we report that exposure of melanoma cells to sub-toxic levels of resveratrol blocked hypoxia-mediated HIF1α stabilization. We also demonstrate that melanoma cells treated with low dose resveratrol for 72 hours show up to a 5-fold increase in p53 and a 2-fold increase in TSP1 levels as detected by western blot and immunohistochemistry. We believe that resveratrol could act as a multifactorial anti-angiogenic agent by inhibiting HIF1α mediated production of pro-angiogenic factors and by upregulating the production of anti-angiogenic factor TSP1. We are currently evaluating the effects of low dose resveratrol on HIF1α, VEGF, p53 and TSP1 expression in the extracellular matrix of three-dimensional melanoma spheroids and co-cultured endothelial cells.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA