Abstract
Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G(1) phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute Disease
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Apoptosis / drug effects
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Benzamides
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Benzoquinones
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Blast Crisis / drug therapy
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Blast Crisis / enzymology
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Blast Crisis / metabolism*
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Blast Crisis / pathology
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Cell Line, Tumor
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Drug Combinations
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Drug Synergism
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Enzyme Inhibitors / pharmacology*
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Gene Deletion
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Gene Expression Regulation
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Histone Deacetylase Inhibitors*
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Humans
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Hydroxamic Acids / analogs & derivatives*
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Hydroxamic Acids / pharmacology*
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Imatinib Mesylate
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Indoles
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K562 Cells
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Lactams, Macrocyclic
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Leukemia, Myeloid / drug therapy
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Leukemia, Myeloid / enzymology
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Leukemia, Myeloid / metabolism*
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Leukemia, Myeloid / pathology
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Panobinostat
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Piperazines / pharmacology
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Point Mutation
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Polyubiquitin / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Pyrimidines / pharmacology
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism
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Rifabutin / analogs & derivatives*
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Rifabutin / pharmacology*
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fms-Like Tyrosine Kinase 3
Substances
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Benzamides
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Benzoquinones
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Drug Combinations
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Enzyme Inhibitors
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HSP90 Heat-Shock Proteins
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Indoles
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Lactams, Macrocyclic
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Piperazines
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Proto-Oncogene Proteins
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Pyrimidines
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Polyubiquitin
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Rifabutin
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tanespimycin
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Imatinib Mesylate
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Panobinostat
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FLT3 protein, human
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Fusion Proteins, bcr-abl
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Proteasome Endopeptidase Complex