Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 333, Issue 3, Pages 1026-1033Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2005.05.191
Keywords
hypoxia; breast cancer; HIF-1 inhibitor; natural product; small molecule; dineolignan; sesquineolignan; manassantin; Saururus cernuus
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Funding
- NCI NIH HHS [R01 CA098787-01A2, CA-95471, P01 CA095471, R01 CA098787-02, R56 CA098787, R01 CA098787, CA-98787-01] Funding Source: Medline
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Hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective therapeutic target for solid tumors. In search of novel small molecule HIF-1 inhibitors, 5400 natural product-rich extracts from plants, marine organisms, and microbes were examined for HIF-1 inhibitory activities using a cell-based reporter assay. Bioassay-guided fractionation and isolation, followed by structure elucidation, yielded three potent natural product-derived HIF-1 inhibitors and two structurally related inactive compounds. In a T47D cell-based reporter assay, manassantin B-1, manassantin A, and 4-O-methylsaucerneol inhibited hypoxia-induced HIF-1 activation with IC50 values of 3, 3, and 20 nM, respectively. All three compounds are relatively hypoxia-specific inhibitors of HIF-1 activation, in comparison to other stimuli. The hypoxic induction of HIF-1 tar.-et genes CDKN1A, VEGF, and GLUT-1 were also inhibited. These compounds inhibit HIF-1 by blocking hypoxia-induced nuclear HIF-1 alpha protein accumulation without affecting HIF-1 alpha mRNA levels. In addition, preliminary structure-activity Studies suggest specific structural requirements for this class of HIF-1 inhibitors. (c) 2005 Elsevier Inc. All rights reserved.
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