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Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist
Bogdan Z. Olenyuk *,
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, DanaFarber Cancer Institute, Harvard Medical School, Boston, MA 02115
Contributed by Peter B. Dervan, October 15, 2004
Vascular endothelial growth factor (VEGF) and its receptorshave been implicated as key factors in tumor angiogenesis thatare up-regulated by hypoxia. We evaluated the effects of DNA-bindingsmall molecules on hypoxia-inducible transcription of VEGF.A synthetic pyrrole-imidazole polyamide designed to bind thehypoxia response element (HRE) was found to disrupt hypoxia-induciblefactor (HIF) binding to HRE. In cultured HeLa cells, this resultedin a reduction of VEGF mRNA and secreted protein levels. Theobserved effects were polyamide-specific and dose-dependent.Analysis of genome-wide effects of the HRE-specific polyamiderevealed that a number of hypoxia-inducible genes were down-regulated.Pathway-based regulation of hypoxia-inducible gene expressionwith DNA-binding small molecules may represent a new approachfor targeting angiogenesis.
Author contributions: B.Z.O., G.-J.Z., W.G.K., and P.B.D. designedresearch; 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.
Transcriptional Up-regulation of Inhibitory PAS Domain Protein Gene Expression by Hypoxia-inducible Factor 1 (HIF-1): A NEGATIVE FEEDBACK REGULATORY CIRCUIT IN HIF-1-MEDIATED SIGNALING IN HYPOXIC CELLS.
Y. Makino, R. Uenishi, K. Okamoto, T. Isoe, O. Hosono, H. Tanaka, A. Kanopka, L. Poellinger, M. Haneda, and C. Morimoto (2007)
J. Biol. Chem.
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Improved nuclear localization of DNA-binding polyamides.