期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 51, 期 24, 页码 8135-8147出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm800873k
关键词
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资金
- National Institutes of Health [CA112314-01A1, AR054005-01]
- Susan G. Komen Foundation [BCTR0503768]
Per-butanoylated N-acetyl-D-mannosamine (Bu(4)ManNAc), a SCFA-hexosamine cancer drug candidate with activity manifest through intact n-butyrate-carbohydrate linkages, reduced the invasion of metastatic MDA-MB-231 breast cancer cells unlike per-butanoylated-D-mannose (Bu(5)Man), a clinically tested compound that did not alter cell mobility. To gain molecular-level insight, therapeutic targets implicated in metastasis were investigated. The active compound Bu(4)ManNAc reduced both MUC1 expression and MMP-9 activity (via down-regulation of CXCR4 transcription), whereas inactive Bu(5)Man had counterbalancing effects on these oncogenes. This divergent impact on transcription was linked to interplay between HDACi activity (held by both Bu(4)ManNAc and Bu(5)Man) and NF-kappa B activity, which was selectively down-regulated by Bu(4)ManNAc. Overall, these results establish a new therapeutic end point (control of invasion) for SCFA-hexosamine hybrid molecules, define relative contributions of molecular players involved in cell mobility and demonstrate that Bu(4)ManNAc breaks the confounding link between beneficial HDACi activity and the simultaneous deleterious activation of NF-kappa B often found in epigenetic drug candidates.
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