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

Shiow Lin Pan, Jih Hwa Guh, Chieh Yu Peng, Shih Wei Wang, Ya Ling Chang, Fong Chi Cheng, Jau Hsiang Chang, Sheng Chu Kuo, Fang Yu Lee, Che Ming Teng

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Abstract

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 Cα 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.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume314
Issue number1
DOIs
Publication statusPublished - Jul 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

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