title: Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells.
abstract: OBJECTIVE
  We determined the effects of vorinostat (suberoylanalide hydroxamic acid) and/or MK-0457 (VX-680), an Aurora kinase inhibitor on the cultured human (HL-60, OCI-AML3, and K562) and primary acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and mutant forms of Bcr-Abl.
  
  
  METHODS
  Following exposure to MK-0457 and/or vorinostat, apoptosis, loss of viability, as well as activity and levels of Aurora kinase and Bcr-Abl proteins were determined.
  
  
  RESULTS
  Treatment with MK-0457 decreased the phosphorylation of Aurora kinase substrates including serine (S)10 on histone H3 and survivin, and led to aberrant mitosis, DNA endoreduplication as well as apoptosis of the cultured human acute leukemia HL-60, OCI-AML3, and K562 cells. Combined treatment with vorinostat and MK-0457 resulted in greater attenuation of Aurora and Bcr-Abl (in K562) kinase activity and levels as well as synergistically induced apoptosis of OCI-AML3, HL-60, and K562 cells. MK-0457 plus vorinostat also induced synergistic apoptosis of BaF3 cells with ectopic overexpression of wild-type or mutant Bcr-Abl. Finally, cotreatment with MK-0457 and vorinostat induced more loss of viability of primary AML and imatinib-refractory CML than treatment with either agent alone, but exhibited minimal toxicity to normal CD34+ progenitor cells.
  
  
  CONCLUSIONS
  Combined in vitro treatment with MK-0457 and vorinostat is highly active against cultured and primary leukemia cells. These findings merit in vivo testing of the combination against human AML and CML cells, especially against imatinib mesylate-resistant Bcr-AblT315I-expressing CML Cells.
authors.affiliation: MCG Cancer Center, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Wang
authors.forename: Rajeshree
authors.initials: R
authors.lastname: Joshi
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Yang
authors.forename: Jianguang
authors.initials: J
authors.lastname: Chen
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kolhe
authors.forename: Ramesh
authors.initials: R
authors.lastname: Balusu
authors.forename: Kelly
authors.initials: K
authors.lastname: Eaton
authors.forename: Pearl
authors.initials: P
authors.lastname: Lee
authors.forename: Celalettin
authors.initials: C
authors.lastname: Ustun
authors.forename: Anand
authors.initials: A
authors.lastname: Jillella
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Stephen
authors.initials: S
authors.lastname: Peiper
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051034:Inhibitor of Apoptosis Proteins; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D000077022:Survivin; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D016044:Fusion Proteins, bcr-abl; D006657:Histones; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D000077022:Survivin; D000077337:Vorinostat; C107489:BIRC5 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines