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: Yuichi Chikaraishi, Masamitsu Shimazawa, Koichi Yokota, Koichiro Yoshino, Hideaki Hara
• Journal: Current neurovascular research (Curr Neurovasc Res) Vol. 6 Issue 3 Pg. 140-7 (Aug 2009) ISSN: 1875-5739 [Electronic] United Arab Emirates
• PMID: 19534723 (Publication Type: Journal Article)

Chemical References

• 3,4,5-trihydroxy-1-(4'-phenoxybenzenesulfonyl)piperidine-2-hydroxy amide
• Angiogenesis Inhibitors
• Enzyme Inhibitors
• Hydroxamic Acids
• Isothiocyanates
• Sulfones
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• isothiocyanic acid
• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human
• Adam17 protein, mouse

Topics

• ADAM Proteins (antagonists & inhibitors)
• ADAM17 Protein
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Animals, Newborn
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Endothelial Cells (drug effects, pathology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Ischemia (complications)
• Isothiocyanates
• Mice
• Mice, Inbred C57BL
• Retinal Neovascularization (etiology, pathology)
• Sulfones (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (adverse effects)