title: Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis.
abstract: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is of physiological and pathological importance. We have investigated the anti-angiogenic potential of two naturally occurring sesterterpenes, leucosesterterpenone (compound 1) and leucosterlactone (compound 2) isolated from the Himalayan plant Leucosceptrum canum and identified as having biological activity in preliminary screening. Compound 1 inhibited fibroblast growth factor-2-induced proliferation, migration in a wounding assay, chemotaxis and tube formation with small vessel (human dermal) and large vessel (bovine aortic) endothelial cells while compound 2 was largely inactive. Both compounds were also active in an in vivo angiogenic model using the chick chorioallantoic membrane. Neither compounds showed inhibitory activity in the absence of fibroblast growth factor-2. We were able to demonstrate in a binding assay that compounds 1 and 2 bound to the fibroblast growth factor-2 receptor-1 with IC(50) values of 1.4 +/- 0.956 and 132.47 +/- 7.90 muM, respectively, with a concomitant down regulation of phosphorylated ERK1/2 but did not bind to receptor-2. Compound 1 was less hydrophobic than compound 2 and this may contribute to its increased activity. Compound 1 is a new addition to the small number of inhibitors of fibroblast growth factor-2-induced angiogenesis. The compound was a specific inhibitor in that it had no effect on vascular endothelial growth factor or epithelial growth factor-induced angiogenesis. Since angiogenesis is essential for tumour development we conclude that these compounds may have potential as anti-tumour agents.
authors.affiliation: School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Chester St., Manchester, M1 5GD, UK.
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.forename: M
authors.initials: M
authors.lastname: Slevin
authors.forename: S
authors.initials: S
authors.lastname: Matou
authors.forename: N
authors.initials: N
authors.lastname: Ahmed
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
authors.forename: R
authors.initials: R
authors.lastname: Ranjit
authors.forename: D
authors.initials: D
authors.lastname: West
authors.forename: J
authors.initials: J
authors.lastname: Gaffney
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011485:Protein Binding; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D054830:Sesterterpenes / Q000378:metabolism / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D054830:Sesterterpenes; D016222:Fibroblast Growth Factor 2; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2