Author
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HOSSAIN, CHOWDHURY - UNIVERSITY OF MISSISSIPPI |
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KIM, YONG-PIL - UNIVERSITY OF MISSISSIPPI |
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Baerson, Scott |
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ZHANG, LEI - UNIV. OF TX-SW MED. CTR. |
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BRUICK, RICHARD - UNIV. OF TX-SW MED. CTR. |
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MOHAMMED, KALEEM - UNIVERSITY OF MISSISSIPPI |
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AGARWAL, AMEETA - UNIVERSITY OF MISSISSIPPI |
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NAGLE, DALE - UNIVERSITY OF MISSISSIPPI |
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ZHOU, YU-DONG - UNIVERSITY OF MISSISSIPPI |
Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 6/13/2005 Publication Date: 8/5/2005 Citation: Hossain, C.F., Kim, Y., Baerson, S.R., Zhang, L., Bruick, R.K., Mohammed, K.A., Agarwal, A.K., Nagle, D.G., Zhou, Y. 2005. Saururus cernuus lignans - potent small molecule inhibitors of hypoxia-inducible factor-1. Biochemical and Biophysical Research Communications. 333(3):1026-1033. Interpretive Summary: Increased expression of the Hypoxia-inducible factor-1 gene is associated with more advanced stages of tumor development. The prognosis for cancer patients showing elevated Hypoxia-inducible factor-1 expression levels is generally not as good as those who do not, since this factor plays a key role in promoting the growth of more advanced-stage tumors. A large repository of plant, marine, and microbial species were screened for the presence of compounds that inhibit Hypoxia-inducible factor-1 expression, as a means of identifying novel natural products with anticancer activity. Three related compounds were identified, manassantin B1, manassantin A, and 4-O-methylsaucerneol, which inhibited Hypoxia-inducible factor-1 gene expression. The expression of genes CDKN1A, VEGF and GLUT-1, which are normally increased by hypoxia-inducible factor-1, were also inhibited by these compounds. Manassantin B1, manassantin A, and 4-O-methylsaucerneol therefore represent novel, potentially anticancer agents, which act by inhibiting the expression of hypoxia-inducible factor-1. Technical Abstract: 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 B1, 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 target genes CDKN1A, VEGF and GLUT-1 were also inhibited. These compounds inhibit HIF-1 by blocking hypoxia-induced nuclear HIF-1a protein accumulation without affecting HIF-1a mRNA levels. In addition, preliminary structure-activity studies suggest specific structural requirements for this class of HIF-1 inhibitors. |