Targeting pro-invasive oncogenes with short chain fatty acid-hexosamine analogues inhibits the mobility of metastatic MDA-MB-231 breast cancer cells

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 MDAMB-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 Bu 4ManNAc. 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.

Original languageEnglish (US)
Pages (from-to)8135-8147
Number of pages13
JournalJournal of medicinal chemistry
Volume51
Issue number24
DOIs
StatePublished - Dec 25 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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