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

Abstract

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-κB activity, which was selectively down-regulated by Bu 4 ManNAc. Overall, these results establish a new therapeutic endpoint (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-κB often found in epigenetic drug candidates.

Metabolic Flux Increases Glycoprotein Sialylation: Implications for Cell Adhesion and Cancer Metastasis

“…Alternately, the sialic acid pathway can be supplemented with exogenous ManNAc but the high levels needed (often in the tens of millimolar (11)) are problematic whereas more efficiently utilized peracetylated analogs (35) have significant and often deleterious side effects (36). The current study avoided these problems by employing the "high flux" tributanoylated analog 1,3,4-O-Bu 3 ManNAc that allows intracellular sialic acid levels to be elevated to high levels (9) with negligible cytotoxicity or perturbation to gene regulation (37,38). In this study, treatment of SW1990 cells with 1,3,4-OBu 3 ManNAc increased total sialic acid levels several fold and impacted glycoconjugate-bound and surface sialylation more modestly (e.g.…”

Renal and Extrarenal Effects of Gum Arabic (Acacia Senegal) - What Can be Learned from Animal Experiments?

“…GA is fermented under the influence of microorganisms in the colon to short chain fatty acids [4], which may counteract inflammation and tumor growth [82,83,84,85]. Moreover, short chain fatty acids have been shown to influence oncogene expression [86,87,88]. …”

Short-Chain Fatty Acid-Modified Hexosamine for Tissue-Engineering Osteoarthritic Cartilage

“…9 To date, this concept has been demonstrated with hexosamines through the ability of n-butanoylated N-acetylmannosamine (ManNAc) analog 3,4,6-O-Bu 3 ManNAc to suppress NFkB and associated metastatic oncogenes in human cancer cell lines. 8 Furthermore, the n-butanoylated GlcNAc analog 3,4,6-OBu 3 GlcNAc also suppressed the NFkB activity in those studies. 8 An attractive feature of this class of compounds is that they minimize toxic non-natural secondary metabolites, but instead are degraded through decomposition to natural byproducts.…”

“…8 Furthermore, the n-butanoylated GlcNAc analog 3,4,6-OBu 3 GlcNAc also suppressed the NFkB activity in those studies. 8 An attractive feature of this class of compounds is that they minimize toxic non-natural secondary metabolites, but instead are degraded through decomposition to natural byproducts. For example, in the case of butanoylated ManNAc, n-butyrate and ManNAc are generated, which can function as histone deacetylase inhibitors or be used for sialic acid biosynthesis, respectively.…”

“…8 This approach builds on an emerging paradigm in drug design, where simple carbohydrates function as novel drug candidates wherein derivation of the core sugar results in defined spatial three-dimensional (3D) structures that can engage proteins to alter the biological activity of a cell. 9 To date, this concept has been demonstrated with hexosamines through the ability of n-butanoylated N-acetylmannosamine (ManNAc) analog 3,4,6-O-Bu 3 ManNAc to suppress NFkB and associated metastatic oncogenes in human cancer cell lines.…”