title: Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist.
abstract: Vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis that are up-regulated by hypoxia. We evaluated the effects of DNA-binding small molecules on hypoxia-inducible transcription of VEGF. A synthetic pyrrole-imidazole polyamide designed to bind the hypoxia response element (HRE) was found to disrupt hypoxia-inducible factor (HIF) binding to HRE. In cultured HeLa cells, this resulted in a reduction of VEGF mRNA and secreted protein levels. The observed effects were polyamide-specific and dose-dependent. Analysis of genome-wide effects of the HRE-specific polyamide revealed that a number of hypoxia-inducible genes were down-regulated. Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis.
authors.affiliation: Division of Chemistry and Chemical Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhang
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Nickols
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A