Targeting Cancer with Gene Expression Inhibitor

Science's STKE  07 Dec 2004:
Vol. 2004, Issue 262, pp. tw443
DOI: 10.1126/stke.2622004tw443

Inhibition of vascular endothelial growth factor (VEGF) signaling is a promising target for anticancer therapies because the growth factor helps cancer cells experiencing hypoxia to promote angiogenesis. Cells respond to hypoxia by activating the hypoxia-inducible factor (HIF), a transcription factor that increases expression of genes (like that for VEGF) that contain hypoxia response elements (HREs). Olenyuk et al. therefore set out to create a small molecule that would inhibit sequence-specific binding of HIF-1 to target genes. They designed a synthetic pyrrole-imidazole polyamide to interact with the HRE in the VEGF promotor. Exposure of cells to the inhibitor at concentrations of 0.2 to 1 micromolar inhibited expression of VEGF mRNA and protein. Microarray analysis of gene expression showed that expression of other HIF-regulated genes was also reduced. With the use of a threshold of a twofold change in expression, the inhibitor altered expression of about 1.5% of the genes monitored. Some genes were commonly affected by the targeted polyamide and a mismatched polyamide control, however. The authors propose that such targeting of hypoxia-induced gene expression might provide a way to inhibit angiogenesis and consequent tumor growth.

B. Z. Olenyuk, G.-J. Zhang, J. M. Klco, N. G. Nickols, W. G. Kaelin Jr., P. B. Dervan, Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc. Natl. Acad. Sci. U.S.A. 101, 16768-16773 (2004). [Abstract] [Full Text]