Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist.
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.
Olenyuk
Bogdan Z
BZ
Division of Chemistry and Chemical Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Zhang
Guo-Jun
GJ
Klco
Jeffery M
JM
Nickols
Nicholas G
NG
Kaelin
William G
WG
Dervan
Peter B
PB
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
D017931:DNA Primers; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A