CB-12181, a New Azasugar-Based Matrix Metalloproteinase/Tumor Necrosis Factor-α Converting Enzyme Inhibitor, Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and Retinal Neovascularization in Vivo

Title: CB-12181, a New Azasugar-Based Matrix Metalloproteinase/Tumor Necrosis Factor-α Converting Enzyme Inhibitor, Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and Retinal Neovascularization in Vivo

Volume: 6 Issue: 3

Author(s): Yuichi Chikaraishi, Masamitsu Shimazawa, Koichi Yokota, Koichiro Yoshino and Hideaki Hara

Affiliation:

Keywords: Human umbilical vein endothelial cells (HUVECs), matrix metalloproteinase (MMP), mice, neovascularization, oxygen-induced retinopathy, retina, TNF-α converting enzyme (TACE)

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-α (TNF-α) 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 μM) 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.

Cite this article as:

Chikaraishi Yuichi, Shimazawa Masamitsu, Yokota Koichi, Yoshino Koichiro and Hara Hideaki, CB-12181, a New Azasugar-Based Matrix Metalloproteinase/Tumor Necrosis Factor-α Converting Enzyme Inhibitor, Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and Retinal Neovascularization in Vivo, Current Neurovascular Research 2009; 6 (3) . https://dx.doi.org/10.2174/156720209788970072