Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells.
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.
Fiskus
Warren
W
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Pranpat
Michael
M
Balasis
Maria
M
Bali
Purva
P
Estrella
Veronica
V
Kumaraswamy
Sandhya
S
Rao
Rekha
R
Rocha
Kathy
K
Herger
Bryan
B
Lee
Francis
F
Richon
Victoria
V
Bhalla
Kapil
K
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
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