title: p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors.
abstract: BACKGROUND
  Histone deacetylase inhibitors (HDACi) are promising antineoplastic agents, but their precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDACi-induced effects has not been fully elucidated. We investigated the anticancer effects of four structurally distinct HDACi, vorinostat, entinostat, apicidin and valproic acid, using isogenic HCT-116 colon cancer cell lines differing in p53 status.
  
  
  METHODS
  Effects were assessed by MTT assay, flow-cytometric analyses of propidium iodide uptake, mitochondrial depolarisation and cell-cycle distribution, as well as by gene expression profiling.
  
  
  RESULTS
  Vorinostat was equally effective in p53 wild-type and null cells, whereas entinostat was less effective in p53 null cells. Histone deacetylase inhibitors treatment suppressed the expression of MDM2 and increased the abundance of p53. Combination treatments showed that vorinostat enhanced the cytotoxic activity of TRAIL and bortezomib, independent of the cellular p53 status. Investigations into the effects of an inhibitor of the sirtuin class of HDAC, tenovin-1, revealed that tenovin-1-mediated cell death hinged on p53.
  
  
  CONCLUSIONS
  These results demonstrate that vorinostat activates p53, but does not require p53 for inducing its anticancer action. Yet they also demonstrate that entinostat-induced cytotoxic effects partially depend on p53, indicating that different HDACi have a different requirement for p53.
authors.affiliation: Department of Paediatric Haematology and Oncology, Jena University Hospital, Children's Clinic, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sonnemann
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Marx
authors.affiliation: Department of Paediatric Haematology and Oncology, Jena University Hospital, Children's Clinic, Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Paediatric Haematology and Oncology, Jena University Hospital, Children's Clinic, Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wittig
authors.affiliation: Department of Paediatric Haematology and Oncology, Jena University Hospital, Children's Clinic, Jena, Germany.
authors.forename: C D
authors.initials: CD
authors.lastname: Palani
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: O H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Department of Paediatric Haematology and Oncology, Jena University Hospital, Children's Clinic, Jena, Germany.
authors.forename: J F
authors.initials: JF
authors.lastname: Beck
mesh_terms: D001549:Benzamides / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000008:administration & dosage; D051736:Proto-Oncogene Proteins c-mdm2; D011725:Pyridines / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000008:administration & dosage; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D011725:Pyridines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C102351:apicidin; C118739:entinostat; D000077337:Vorinostat; D014635:Valproic Acid; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2