o-(chloroacetylcarbamoyl)fumagillol and monorden

The recent use of chemical genomics to identify bioactive small molecules that interact with specific proteins has had a tremendous impact on both the functional analysis of genes and drug development. Accordingly, the current review focuses on the utilization of this new research engine in the target identification and validation of anti-angiogenic agents capable of regulating the growth and spread of cancer cells. In addition, the use of chemical genomics to discover novel anti-angiogenic agent targets and to validate their biological relevancy is providing new insights into the biological role of targets in angiogenesis as well as advancing the development of new anti-angiogenic agents.

Topics: Angiogenesis Inhibitors; Cyclohexanes; Drug Delivery Systems; Drug Design; Genomics; Histone Deacetylase Inhibitors; Histone Deacetylases; HSP90 Heat-Shock Proteins; Humans; Lactones; Macrolides; O-(Chloroacetylcarbamoyl)fumagillol; Research; Sesquiterpenes

Angiogenesis consists of endothelial cell proliferation, migration and tube formation. It is useful to investigate endothelial cell behavior using immortalized endothelial cell lines. We characterized cell growth property, growth factor dependency and response to angioinhibitory drugs; TNP-470, staurosporine, radicicol and genistein, using human umbilical vein endothelial cells (HUVECs) immortalized by human papilloma virus (HPV)-16 E6-E7, named HUVECs/E6-E7, and HUVECs/E6-E7 transformed by v-Ki-ras gene, named HUVECs/E6-E7/ras. The dependency to vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) for cell proliferation decreased in HUVECs/E6-E7, but were restored in HUVECs/E6-E7/ras. Flow cytometric analysis demonstrated that a VEGF receptor KDR/flk-1 was down-regulated in HUVECs/E6-E7 but not in HUVECs/E6-E7/ras. Expression of another VEGF receptor flt-1 was consistent in all cells including HUVECs, HUVECs/E6-E7 and HUVECs/E6-E7/ras. According to the analysis of the angioinhibitory drugs, HUVECs/E6-E7 was obviously resistant to TNP-470, but HUVECs/E6-E7/ras showed similar response compared to HUVECs which suggests that v-Ki-ras signaling pathway is associated with VEGF receptor expression and make HUVECs/E6-E7 sensitive to TNP-470 by modulating the signal transduction cascade. In conclusion, HPV-16 E6-E7 and v-Ki-ras genes have unique growth properties and these immortalized cells are useful for investigating signal transduction pathways of endothelial cells, and for screening of angioinhibitory drugs.

Topics: Angiogenesis Inhibitors; Cell Division; Cell Line, Transformed; Cell Transformation, Viral; Cyclohexanes; Cytokines; Drug Screening Assays, Antitumor; Endothelium, Vascular; Enzyme Inhibitors; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genes, ras; Genistein; Humans; Lactones; Macrolides; Neoplasm Proteins; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Oncogene Protein p21(ras); Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Repressor Proteins; Sesquiterpenes; Signal Transduction; Staurosporine; Umbilical Veins