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PNAS 101 (48): 16768-16773

Copyright © 2004 by the National Academy of Sciences.


Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist

Bogdan Z. Olenyuk *, Guo-Jun Zhang {dagger}, Jeffery M. Klco {dagger}, Nicholas G. Nickols *, William G. Kaelin, Jr. {dagger}, {ddagger}, and Peter B. Dervan *, {ddagger}

*Division of Chemistry and Chemical Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125; and {dagger}Department of Adult Oncology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02115

Contributed by Peter B. Dervan, October 15, 2004

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.

Key Words: gene regulation • hypoxia-inducible factor • polyamide

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.

Abbreviations: HIF, hypoxia-inducible factor; ARNT, aryl hydrocarbon receptor nuclear translocator; HRE, hypoxia response element; DFO, desferrioxamine mesylate; ET, endothelin.

{ddagger} To whom correspondence may be addressed. E-mail: william_kaelin{at} or dervan{at}

© 2004 by The National Academy of Sciences of the USA

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