title: Targeting glycosylation pathways and the cell cycle: sugar-dependent activity of butyrate-carbohydrate cancer prodrugs.
abstract: 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.
authors.affiliation: Whiting School of Engineering, Clark Hall 106A, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
authors.forename: Srinivasa-Gopalan
authors.initials: SG
authors.lastname: Sampathkumar
authors.forename: Mark B
authors.initials: MB
authors.lastname: Jones
authors.forename: M Adam
authors.initials: MA
authors.lastname: Meledeo
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Campbell
authors.forename: Sean S
authors.initials: SS
authors.lastname: Choi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hida
authors.forename: Prasra
authors.initials: P
authors.lastname: Gomutputra
authors.forename: Anthony
authors.initials: A
authors.lastname: Sheh
authors.forename: Tim
authors.initials: T
authors.lastname: Gilmartin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Head
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Yarema
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006031:Glycosylation; D006367:HeLa Cells; D006595:Hexosamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D002087:Butyrates; D006595:Hexosamines; D011355:Prodrugs; C002022:N-acetylmannosamine