title: HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.
abstract: OBJECTIVE
  The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM).
  
  
  METHODS
  Bcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model.
  
  
  RESULTS
  Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K).
  
  
  CONCLUSIONS
  HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.
authors.affiliation: Division of Hematology/Oncology, Department of Biochemistry, and Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, Virginia 23298, USA.
authors.forename: Tri
authors.initials: T
authors.lastname: Nguyen
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Elisa
authors.initials: E
authors.lastname: Attkisson
authors.forename: Lora
authors.initials: L
authors.lastname: Kramer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jordan
authors.forename: Nguyen
authors.initials: N
authors.lastname: Nguyen
authors.forename: Nikhil
authors.initials: N
authors.lastname: Kolluri
authors.forename: Markus
authors.initials: M
authors.lastname: Muschen
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D007191:Indazoles; C543891:KW 2449; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl