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.
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 alpha 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.
Pan
Shiow-Lin
SL
Pharmacological Institute, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei, Taiwan.
Guh
Jih-Hwa
JH
Peng
Chieh-Yu
CY
Wang
Shih-Wei
SW
Chang
Ya-Ling
YL
Cheng
Fong-Chi
FC
Chang
Jau-Hsiang
JH
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008136:Longevity; D008870:Microtubules / Q000187:drug effects; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D013936:Thymidine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D020536:Enzyme Activators; D007191:Indazoles; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D006162:Guanylate Cyclase; C022616:thiazolyl blue; D013936:Thymidine