TY - JOUR
T1 - Targeting Glycosylation Pathways and the Cell Cycle
T2 - Sugar-Dependent Activity of Butyrate-Carbohydrate Cancer Prodrugs
AU - Sampathkumar, Srinivasa Gopalan
AU - Jones, Mark B.
AU - Meledeo, M. Adam
AU - Campbell, Christopher T.
AU - Choi, Sean S S.
AU - Hida, Kaoru
AU - Gomutputra, Prasra
AU - Sheh, Anthony
AU - Gilmartin, Tim
AU - Head, Steven R.
AU - Yarema, Kevin J.
N1 - Funding Information:
We are grateful to K. Konstantopoulos for flow cytometer access, B. Vogelstein (Johns Hopkins Medical Institute [JHMI]) for the kind gift of luc-p21 WAF1/Cip1 plasmid, R.E. McCarty for luminometer access, and L. Blosser (JHMI) for help with cell cycle studies. Funding was from the Arnold and Mabel Beckman Foundation, the National Institutes of Health (1R01CA112314-01A1), and the National Science Foundation (QSB-0425668). The Gene Microarray Core resources and collaborative efforts were provided by The Consortium for Functional Glycomics, funded by NIGMS-GM62116.
PY - 2006/12
Y1 - 2006/12
N2 - 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.
AB - 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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U2 - 10.1016/j.chembiol.2006.09.016
DO - 10.1016/j.chembiol.2006.09.016
M3 - Article
C2 - 17185222
AN - SCOPUS:33845518649
SN - 1074-5521
VL - 13
SP - 1265
EP - 1275
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 12
ER -