Targeting glycosylation pathways and the cell cycle: sugar-dependent activity of butyrate-carbohydrate cancer prodrugs |
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Authors: | Sampathkumar Srinivasa-Gopalan Jones Mark B Meledeo M Adam Campbell Christopher T Choi Sean S Hida Kaoru Gomutputra Prasra Sheh Anthony Gilmartin Tim Head Steven R Yarema Kevin J |
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Affiliation: | Whiting School of Engineering, Clark Hall 106A, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA. |
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Abstract: | 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 (But4ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-D-glucosamine (But4GlcNAc, 2), D-mannose (But5Man, 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 p21WAF1/Cip1 expression, 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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