title: Amidation inhibitors 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester are novel HDAC inhibitors with anti-tumorigenic properties.
abstract: 4-Phenyl-3-butenoic acid (PBA) is an inhibitor of peptidylglycine alpha-amidating monooxygenase with anti-inflammatory properties that has been shown to inhibit the growth of ras-mutated epithelial and human lung carcinoma cells. In this report, we show that PBA also increases the acetylation levels of selected histone subtypes in a dose and time dependent manner, an effect that is attributable to the inhibition of histone deacetylase (HDAC) enzymes. Comparison studies with the known HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) using high resolution two-dimensional polyacrylamide gels and Western analysis provide evidence that PBA acts as an HDAC inhibitor within cells. PBA and a more potent amidation inhibitor, 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester (AOPHA-Me), inhibit HDAC enzymes in vitro at micromolar concentrations, with IC50 values approximately 30 fold lower for AOPHA-Me than PBA for selected HDAC isoforms. Overall, these results indicate that PBA and AOPHA-Me are novel anti-tumorigenic HDAC inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA, 30341, USA.
authors.forename: Amna
authors.initials: A
authors.lastname: Ali
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Burns
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Lucrezi
authors.forename: Sheldon W
authors.initials: SW
authors.lastname: May
authors.forename: George R
authors.initials: GR
authors.lastname: Green
authors.forename: Diane F
authors.initials: DF
authors.lastname: Matesic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002208:Caproates / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D000077337:Vorinostat
chemical_list: C518642:5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester; D000970:Antineoplastic Agents; D002208:Caproates; D005229:Fatty Acids, Monounsaturated; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C064180:4-phenyl-3-butenoic acid; D000077337:Vorinostat; D006655:Histone Deacetylases