Publications [#210114] of Mark W. Dewhirst

Papers Published

1. GM Palmer, Z Tiran, Z Zhou, ME Capozzi, W Park, C Coletta, A Pyriochou, Y Kliger, O Levy, I Borukhov, MW Dewhirst, G Rotman, JS Penn, A Papapetropoulos, A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization., British journal of pharmacology, vol. 165 no. 6 (March, 2012), pp. 1891-903, ISSN 1476-5381 [doi]
   (last updated on 2012/10/26)

   Abstract:
   OBJECTIVE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. METHODS: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.

   Keywords:
   Angiogenesis Inhibitors • Angiopoietins • Animals • Cell Movement • Chickens • Chorioallantoic Membrane • Colorectal Neoplasms • Disease Models, Animal • Female • HCT116 Cells • Human Umbilical Vein Endothelial Cells • Humans • Mice • Mice, Nude • Neovascularization, Pathologic • Peptides • Rats • Rats, Sprague-Dawley • Retinal Neovascularization • Xenograft Model Antitumor Assays • blood supply • drug effects • drug therapy* • metabolism • pathology • pharmacology • physiology • therapeutic use*