title: Differential protein acetylation induced by novel histone deacetylase inhibitors.
abstract: Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.
authors.affiliation: Cancer Research R47J-AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA. keith.glaser@abbott.com
authors.forename: K B
authors.initials: KB
authors.lastname: Glaser
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: L J
authors.initials: LJ
authors.lastname: Pease
authors.forename: M J
authors.initials: MJ
authors.lastname: Staver
authors.forename: P A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: R R
authors.initials: RR
authors.lastname: Frey
authors.forename: R B
authors.initials: RB
authors.lastname: Garland
authors.forename: H R
authors.initials: HR
authors.lastname: Heyman
authors.forename: C K
authors.initials: CK
authors.lastname: Wada
authors.forename: A
authors.initials: A
authors.lastname: Vasudevan
authors.forename: M R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: S K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: M L
authors.initials: ML
authors.lastname: Curtin
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors; D005354:Fibrosarcoma / Q000201:enzymology* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006655:Histone Deacetylases