Work

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

Year: 2004

Type: article

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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.0407617101

Authors: Bogdan Z. Olenyuk, Guo-Jun Zhang, Jeffery M. Klco, Nicholas G. Nickols, William G. Kaelin, Peter B. Dervan

Institutions: California Institute of Technology, Harvard University, Dana-Farber Cancer Institute

Language: English

Topic: Angiogenesis and VEGF in Cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W2000975094

FWCI: 5.266

Cites: 48

Cited by: 220

Related to: 10