Journal
CHEMISTRY & BIOLOGY
Volume 13, Issue 12, Pages 1265-1275Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2006.09.016
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Funding
- NCI NIH HHS [1R01CA112314-01A1] Funding Source: Medline
- NIGMS NIH HHS [GM62116] Funding Source: Medline
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Short-chain fatty acid (SCFA)-carbohydrate hybrid molecules that target both histone deacetylation and glycosylation pathways to achieve sugar-dependent activity against cancer cells are described in this article. Specifically, n-butyrate esters of N-acetyl-D-mannosamine (But(4)ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-D-glucosamine (But(4)GlcNAc, 2), D-mannose (But(5)Man, 3), or glycerol (tributryin, 4) derivatives only provided transient cell cycle arrest. Western blots, reporter gene assays, and cell cycle analysis established that n-butyrate, when delivered to cells via any carbohydrate scaffold, functioned as a histone deacetylase inhibitor (HDACi), upregulated p21(WAF1/Cip1) expressions and inhibited proliferation. However, only 1, a compound that primed sialic acid biosynthesis and modulated the expression of a different set of genes compared to 3, ultimately killed the cells. These results demonstrate that the biological activity of butyrate can be tuned by sugars to improve its anticancer properties.
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