title: Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells.
abstract: BACKGROUND
  The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the Bcr-Abl inhibitor imatinib in imatinib-resistant cell lines.
  
  
  METHODS
  Interactions between imatinib, and valproate have been examined in imatinib-sensitive and -resistant chronic myeloid leukemia (CML)cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients.
  
  
  RESULTS
  In imatinib-sensitive cell lines, cotreatment with imatinib 0.5 muM and valproate 5 microM for 48 hours potently enhanced imatinib-induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib-rsistant patients, valproate restored sensitivity to the cytotoxic effects of imatinib. Coexposure of cells to valproate and imatinib was associated with repression of several genes involved in Bcr-Abl transformation. In particular, the combination valproate-imatinib downregulated the expression of Bcr-Abl and the antiapoptotic protein Bcl-2, which is particularly overexpressed in imatinib-resistant clones.
  
  
  CONCLUSIONS
  Data from this study suggested that administration of the clinically available HDAC inhibitor valproate may be a powerful strategy to enhance cytotoxic effects of imatinib in those patient resistant to imatinib or in which complete cytogenetic remission has been not reached.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. alessandromorotti@yahoo.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Francesca
authors.initials: F
authors.lastname: Messa
authors.forename: Francesca
authors.initials: F
authors.lastname: Arruga
authors.forename: Ilaria
authors.initials: I
authors.lastname: Defilippi
authors.forename: Sonia
authors.initials: S
authors.lastname: Carturan
authors.forename: Renata
authors.initials: R
authors.lastname: Catalano
authors.forename: Valentina
authors.initials: V
authors.lastname: Rosso
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiarenza
authors.forename: Chiara
authors.initials: C
authors.lastname: Pilatrino
authors.forename: Angelo
authors.initials: A
authors.lastname: Guerrasio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Taulli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bracco
authors.forename: Marisa
authors.initials: M
authors.lastname: Pautasso
authors.forename: Daniela
authors.initials: D
authors.lastname: Baraban
authors.forename: Enrico
authors.initials: E
authors.lastname: Gottardi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D014635:Valproic Acid; D000068877:Imatinib Mesylate