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

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-(5Ј-hydroxymethyl-2Ј-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 [ 3 H]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 Ͼ 175%) without cytotoxicity. YC-1 may be useful for treating angiogenesis-dependent human diseases such as cancer.

CLC604 preferentially inhibits the growth of HER2-overexpressing cancer cells and sensitizes these cells to the inhibitory effect of Taxol in vitro and in vivo

“…Furthermore, YC-1 was observed to suppress NF-κB activity via inhibition of the phosphorylation and degradation of I-κBα and to induce apoptosis in prostate cancer PC-3 cells (17). Moreover, YC-1 was recognized to inhibit angiogenesis via repression of VEGF by downregulating HIF-1 resulting in reducing cancer cell proliferation (16,(29)(30)(31). In the present study, our results showed that YC-1 repressed the protein level of HER2.…”

“…In vivo xenograft studies have also revealed that YC-1 exhibits marked antitumor activity against various cancer cell lines and prolongs the survival time of tumor-bearing mice, but without evident toxic effects (16,17). The anticancer effect of YC-1 appears to be a consequence of its multiple actions, including anti-inflammation activity, suppression of the hypoxia-inducible factor-1α (HIF-1α) expression, influence on the differentiation of stem cells, and promotion of NK cell differentiation by activating the p38-MAPK pathway (18)(19)(20).…”

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

“…Immunoprecipitation and Western Blot Analysis Nuclear and mitochondrial fractionation were done as described previously (19). Total protein was determined and equal amounts of protein were separated by 10-15% SDS-PAGE and immunoblotted with specific primary antibodies.…”

YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia

“…More recently, YC-1 was reported to decrease hypoxia-induced HIF-1a accumulation and expression of downstream HIF-1 target genes, including those for vascular endothelial growth factor (VEGF) and erythropoietin, in vitro (Chun et al, 2001) and to inhibit angiogenesis and tumor growth in animals (Yeo et al, 2003;Pan et al, 2005). Although YC-1 has become a valuable research tool for studies of HIF-1a (Moeller et al, 2004;Funasaka et al, 2005), the mechanism by which YC-1 exerts its antitumor effects has not been established.…”