title: Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells.
abstract: OBJECTIVE
  We determined the effects of vorinostat [suberoylanilide hydroxamic acid (SAHA)] and/or dasatinib, a dual Abl/Src kinase (tyrosine kinase) inhibitor, on the cultured human (K562 and LAMA-84) or primary chronic myelogenous leukemia (CML) cells, as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and kinase domain-mutant forms of Bcr-Abl.
  
  
  METHODS
  Following exposure to dasatinib and/or vorinostat, apoptosis, loss of clonogenic survival, as well as the activity and levels of Bcr-Abl and its downstream signaling proteins were determined.
  
  
  RESULTS
  Treatment with dasatinib attenuated the levels of autophosphorylated Bcr-Abl, p-CrkL, phospho-signal transducer and activator of transcription 5 (p-STAT5), p-c-Src, and p-Lyn; inhibited the activity of Lyn and c-Src; and induced apoptosis of the cultured CML cells. Combined treatment of cultured human CML and BaF3 cells with vorinostat and dasatinib induced more apoptosis than either agent alone, as well as synergistically induced loss of clonogenic survival, which was associated with greater depletion of Bcr-Abl, p-CrkL, and p-STAT5 levels. Cotreatment with dasatinib and vorinostat also attenuated the levels of Bcr-AblE255K and Bcr-AblT315I and induced apoptosis of BaF3 cells with ectopic expression of the mutant forms of Bcr-Abl. Finally, cotreatment of the primary CML cells with vorinostat and dasatinib induced more loss of cell viability and depleted Bcr-Abl or Bcr-AblT315I, p-STAT5, and p-CrkL levels than either agent alone.
  
  
  CONCLUSIONS
  As shown here, the preclinical in vitro activity of vorinostat and dasatinib against cultured and primary CML cells supports the in vivo testing of the combination in imatinib mesylate-sensitive and imatinib mesylate-resistant CML cells.
authors.affiliation: Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Michael
authors.initials: M
authors.lastname: Pranpat
authors.forename: Maria
authors.initials: M
authors.lastname: Balasis
authors.forename: Purva
authors.initials: P
authors.lastname: Bali
authors.forename: Veronica
authors.initials: V
authors.lastname: Estrella
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kumaraswamy
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Kathy
authors.initials: K
authors.lastname: Rocha
authors.forename: Bryan
authors.initials: B
authors.lastname: Herger
authors.forename: Francis
authors.initials: F
authors.lastname: Lee
authors.forename: Victoria
authors.initials: V
authors.lastname: Richon
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; D000077337:Vorinostat; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib