title: Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis.
abstract: 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 microM 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 muM 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Chemistry, Biology and Health Sciences, Manchester Metropolitan University, Chester St, Manchester, UK. shussain@gmail.com
authors.forename: Sajjad
authors.initials: S
authors.lastname: Hussain
authors.forename: Mark
authors.initials: M
authors.lastname: Slevin
authors.forename: Nessar
authors.initials: N
authors.lastname: Ahmed
authors.forename: David
authors.initials: D
authors.lastname: West
authors.forename: Muhammad Iqbal
authors.initials: MI
authors.lastname: Choudhary
authors.forename: Humera
authors.initials: H
authors.lastname: Naz
authors.forename: John
authors.initials: J
authors.lastname: Gaffney
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D029403:Burseraceae / Q000737:chemistry; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005960:Glucosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D005960:Glucosides; D006027:Glycosides; D013267:Stilbenes; C541649:trans-4',5'-dihydroxy-3-methoxystilbene-5-O-(alpha-L-rhamnopyranosyl-(1-2)-(alpha-L-rhamnopyranosyl-(1-6))-beta-D-glucopyranoside); D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048052:Mitogen-Activated Protein Kinase 3