Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis

Background: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1 -> 2)-[alpha-L-rhamnopyranosyl-(1 -> 6)}-beta-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. Results: Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 +/- 0.18 - 48.90 +/- 0.40 mu M but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 +/- 1.04 and 9.32 +/- 0.082 mu M respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. Conclusion: Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis