semaxinib and thiazolyl-blue

Ovarian cancer has the highest mortality rate of any gynecological disease affecting women in Western countries. VEGF is a crucial inducer of angiogenesis both in vivo and in vitro. VEGF is commonly upregulated in ovarian cancer and is regulated by HIF-1. SU5416 is known to inhibit various stages of tumor growth. In this study, we show that SU5416 inhibited VEGF mRNA expression in ovarian cancer cells in a dose-dependent manner. SU5416 inhibited VEGF expression at the transcriptional level through the HIF-1 DNA binding site. HIF-1 is composed of HIF-1alpha and HIF-1beta subunits. SU5416 specifically decreased HIF-1alpha, but not HIF-1beta protein levels. To understand the signaling pathways regulating SU5416-inhibited VEGF and HIF-1alpha expression, we found that SU5416 inhibited PI3K activity. AKT is a downstream target of PI3K. We found that SU5416 also inhibited AKT and p70S6K1 activation and activity in a dose-dependent manner. These results demonstrate that SU5416 inhibited VEGF and HIF-1alpha expression through the inhibition of PI3K/AKT/p70S6K1 pathway in ovarian cancer cells. These results indicate that SU5416 may be an effective agent for ovarian cancer treatment through the inhibition of VEGF and HIF-1 expression, and the activation of PI3K/AKT/p70S6K1 signaling pathway.

Topics: Binding Sites; Blotting, Northern; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Indoles; Luciferases; Neovascularization, Pathologic; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Plasmids; Protein Binding; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyrroles; Ribosomal Protein S6 Kinases, 70-kDa; RNA; RNA, Messenger; Signal Transduction; Tetrazolium Salts; Thiazoles; Time Factors; Transcription Factors; Transcriptional Activation; Transfection; Up-Regulation; Vascular Endothelial Growth Factor A