Targeting Pro-Invasive Oncogenes with Short Chain Fatty Acid-Hexosamine Analogues Inhibits the Mobility of Metastatic MDA-MB-231 Breast Cancer Cells

详细信息    查看全文

• 作者：Christopher T. Campbell ; Udayanath Aich ; Christopher A. Weier ; Jean J. Wang ; Sean S. Choi ; Mary M. Wen ; Katharina Maisel ; Srinivasa-Gopalan Sampathkumar ; Kevin J. Yarema
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：8135-8147
• 全文大小：566K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

Per-butanoylated N-acetyl-d-mannosamine (Bu₄ManNAc), 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 (Bu₅Man), 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 Bu₄ManNAc reduced both MUC1 expression and MMP-9 activity (via down-regulation of CXCR4 transcription), whereas “inactive” Bu₅Man had counterbalancing effects on these oncogenes. This divergent impact on transcription was linked to interplay between HDACi activity (held by both Bu₄ManNAc and Bu₅Man) and NF-κB activity, which was selectively down-regulated by Bu₄ManNAc. 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 Bu₄ManNAc breaks the confounding link between beneficial HDACi activity and the simultaneous deleterious activation of NF-κB often found in epigenetic drug candidates.