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Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.

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.
AuthorsPrince George, Purva Bali, Srinivas Annavarapu, Anna Scuto, Warren Fiskus, Fei Guo, Celia Sigua, Gautam Sondarva, Lynn Moscinski, Peter Atadja, Kapil Bhalla
JournalBlood (Blood) Vol. 105 Issue 4 Pg. 1768-76 (Feb 15 2005) ISSN: 0006-4971 [Print] United States
PMID15514006 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Benzamides
  • Benzoquinones
  • Drug Combinations
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Lactams, Macrocyclic
  • Piperazines
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Polyubiquitin
  • Rifabutin
  • tanespimycin
  • Imatinib Mesylate
  • Panobinostat
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Fusion Proteins, bcr-abl
  • Proteasome Endopeptidase Complex
Topics
  • Acute Disease
  • Apoptosis (drug effects)
  • Benzamides
  • Benzoquinones
  • Blast Crisis (drug therapy, enzymology, metabolism, pathology)
  • Cell Line, Tumor
  • Drug Combinations
  • Drug Synergism
  • Enzyme Inhibitors (pharmacology)
  • Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
  • Gene Deletion
  • Gene Expression Regulation
  • HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids (analogs & derivatives, pharmacology)
  • Imatinib Mesylate
  • Indoles
  • K562 Cells
  • Lactams, Macrocyclic
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, metabolism, pathology)
  • Leukemia, Myeloid (drug therapy, enzymology, metabolism, pathology)
  • Panobinostat
  • Piperazines (pharmacology)
  • Point Mutation
  • Polyubiquitin (metabolism)
  • Proteasome Endopeptidase Complex (metabolism)
  • Proto-Oncogene Proteins (genetics, metabolism)
  • Pyrimidines (pharmacology)
  • Receptor Protein-Tyrosine Kinases (genetics, metabolism)
  • Rifabutin (analogs & derivatives, pharmacology)
  • fms-Like Tyrosine Kinase 3

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