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CARDIOVASCULAR

YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] Inhibits Endothelial Cell Functions Induced by Angiogenic Factors in Vitro and Angiogenesis in Vivo Models

Pharmacological Institute (S.-L.P., C.-Y.P., S.-W.W., Y.-L.C., C.-M.T.) and School of Pharmacy (J.-H.G.), College of Medicine, National Taiwan University, Taipei, Taiwan; MDS Pharma Service, Taipei, Taiwan (F.-C.C.); Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan (S.-C.K.); and Yung-Shin Pharmaceutical Industry Co., Ltd., Taichung, Taiwan (J.-H.C., F.-Y.L.)

Angiogenesis is a process that involves endothelial cell proliferation, migration, invasion, and tube formation, and inhibition of these processes has implications for angiogenesis-mediated disorders. The purpose of this study was to evaluate the antiangiogenic efficacy of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] in well characterized in vitro and in vivo systems. YC-1 inhibited the ability of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in a dose-dependent manner to induce proliferation, migration, and tube formation in human umbilical vascular endothelial cells; these outcomes were evaluated using [³H]thymidine incorporation, transwell chamber, and Matrigel-coated slide assays, respectively. YC-1 inhibited VEGF- and bFGF-induced p42/p44 mitogen-activated protein kinase and Akt phosphorylation as well as protein kinase C translocation using Western blot analysis. The effect of YC-1 on angiogenesis in vivo was evaluated using the mouse Matrigel implant model. YC-1 administered orally in doses of 1 to 100 mg/kg/day inhibited VEGF- and bFGF-induced neovascularization in a dose-dependent manner over 7 days. These results indicate that YC-1 has antiangiogenic activity at very low doses. Moreover, in transplantable murine tumor models, YC-1 administered orally displayed a high degree of antitumor activity (treatment-to-control life span ratio > 175%) without cytotoxicity. YC-1 may be useful for treating angiogenesis-dependent human diseases such as cancer.

Address correspondence to: Dr. Che-Ming Teng, Pharmacological Institute, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei, Taiwan. E-mail: cmteng{at}ha.mc.ntu.edu.tw

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