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 HIRE. 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 HIRE-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.
Additional Information
© 2004 by the National Academy of Sciences. Contributed by Peter B. Dervan, October 15, 2004. Published online before print November 19, 2004, 10.1073/pnas.0407617101 We thank the National Institutes of Health for support. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering of California Institute of Technology, supported in part by the National Science Foundation Materials Research Science and Engineering program. Oligonucleotide microarray experiments were performed in the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. Author contributions: B.Z.O., G.-J.Z., W.G.K., and P.B.D. designed research; B.Z.O., G.-J.Z., J.M.K., and N.G.N. performed research; B.Z.O., N.G.N., W.G.K., G.-J.Z., and P.B.D. analyzed data; B.Z.O., G.-J.Z., N.G.N., W.G.K., and P.B.D. wrote the paper.Attached Files
Published - OLEpnas04.pdf
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Additional details
- PMCID
- PMC534742
- Eprint ID
- 951
- Resolver ID
- CaltechAUTHORS:OLEpnas04
- NIH
- NSF
- Created
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2005-11-15Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field