title: Angiogenesis inhibition by the maleimide-based small molecule GNX-686.
abstract: We investigated the anti-angiogenic properties of GNX-686, a newly identified maleimide-based small molecule. In vitro studies on HUVEC showed that GNX-686 inhibited cell growth with an ED(50) of 20-25 μM, while human HeLa tumor cells and non-transformed embryonic mouse fibroblasts were less sensitive for the drug. More importantly, at 4 μM, a concentration that was non-toxic to any cell in culture, GNX-686 showed a significant inhibitory effect on tube formation by HUVEC, indicating a profound anti-angiogenic activity. Angiogenesis inhibition was subsequenly tested in the chorioallantoic membrane (CAM) of the chicken embryo. A significant angiostatic activity was observed in the CAM model, and results were compared with the effect of bevacizumab, a well known and clinically used VEGF inhibitor. Under our experimental conditions, GNX-686 was found to be as effective as bevacizumab, significantly changing the morphology of the vascular network, as illustrated and quantified by the relative number of branching points and the relative mean mesh size of the vascular network. In another in vivo model of neovascularization, the mouse retinopathy of prematurity (ROP), the vascular network of GNX-686-treated mice was significantly altered, reducing the density of the retinal microvasculature, as compared to the control retinas. Immunohistochemical processing of the GNX-686 treated (4μM) eyes showed over 50% reduction of the number of cell nuclei associated with neovasculature, as compared to the control-treated eye. Taken together these results demonstrate that GNX-686 is a promising anti-angiogenic compound that could be developed for the treatment of diseases characterized by aberrant angiogenesis such as ocular pathologies and cancer.
authors: Medical Photonics Group, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland. Patrycja.Nowak-Sliwinska@epfl.ch
authors: Patrycja
authors: P
authors: Nowak-Sliwinska
authors: Mariangela
authors: M
authors: Storto
authors: Tiziana
authors: T
authors: Cataudella
authors: Jean-Pierre
authors: JP
authors: Ballini
authors: Randall
authors: R
authors: Gatz
authors: Marco
authors: M
authors: Giorgio
authors: Hubert
authors: H
authors: van den Bergh
authors: Simon
authors: S
authors: Plyte
authors: Georges
authors: G
authors: Wagnières
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply* / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015861:Retinal Neovascularization / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C572527:GNX-686; D008301:Maleimides; D000068258:Bevacizumab