"Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist ( gene regulation / hypoxia-inducible factor / polyamide )
Bogdan Z. Olenyuk *, Guo-Jun Zhang , Jeffery M. Klco , Nicholas G. Nickols *, William G. Kaelin Jr. , and Peter B. Dervan * *Division of Chemistry and Chemical Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125; and Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
Contributed by Peter B. Dervan, October 15, 2004
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."
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