title: CB-12181, a new azasugar-based matrix metalloproteinase/tumor necrosis factor-alpha converting enzyme inhibitor, inhibits vascular endothelial growth factor-induced angiogenesis in vitro and retinal neovascularization in vivo.
abstract: To evaluate the anti-angiogenic efficacy of CB-12181 [an azasugar derivative that has inhibitory actions against matrix metalloproteinases (MMPs) and tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE)], we investigated the suppressing ability on in vitro (tube formation by endothelial cells) and in vivo (retinal neovascularization on murine ischemia-induced proliferative retinopathy) models of angiogenesis. For in vitro analysis, a capillary-like tube formation model using human umbilical vein endothelial cells (HUVECs) and fibroblasts co-culture assay was employed. Tube formation of HUVECs was stimulated by vascular endothelial growth factor (VEGF) and incubated with different concentrations of CB-12181 (0.1-100 microM) for 11 days. For in vivo analysis, mice were exposed to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Then, the mice were removed from the oxygen treatment and treated with CB-12181 (1, 15, or 50 mg/kg) by daily subcutaneous injection from the time of reintroduction to room air at P12 until P16. At P17, pathological and physiological angiogenesis was quantified using retinal flat-mounts visualized by fluorescent angiography. In the in vitro angiogenesis model, CB-12181 significantly suppressed VEGF-induced HUVEC tube formation. Furthermore, in the in vivo angiogenesis model, administration of CB-12181 significantly suppressed retinal neovascularization without any apparent side effects on physiological revascularization to the oxygen-induced obliteration area. These results suggest that CB-12181 might be useful in the treatment of various diseases that depend on pathologic angiogenesis, and especially valuable for the treatment of diabetic retinopathy and retinopathy of prematurity.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Mitahora-higashi, Gifu, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Chikaraishi
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokota
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yoshino
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007511:Ischemia / Q000150:complications; D017879:Isothiocyanates; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000209:etiology* / Q000473:pathology*; D013450:Sulfones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects*
chemical_list: C485105:3,4,5-trihydroxy-1-(4'-phenoxybenzenesulfonyl)piperidine-2-hydroxy amide; D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D017879:Isothiocyanates; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C037152:isothiocyanic acid; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse