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Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3.

AbstractPURPOSE:
Mutant FLT-3 receptor tyrosine kinase is a client protein of the molecular chaperone heat shock protein 90 and is commonly present and contributes to the leukemia phenotype in acute myelogenous leukemia (AML). LAQ824, a cinnamyl hydroxamate histone deacetylase inhibitor, is known to induce acetylation and inhibition of heat shock protein 90. Here, we determined the effects of LAQ824 and/or PKC412 (a FLT-3 kinase inhibitor) on the levels of mutant FLT-3 and its downstream signaling, as well as growth arrest and cell-death of cultured and primary human AML cells.
EXPERIMENTAL DESIGN:
The effect of LAQ824 and/or PKC412 treatment was determined on the levels of FLT-3 and phosphorylated (p)-FLT-3, on downstream pro-growth and pro-survival effectors, e.g., p-STAT5, p-AKT, and p-extracellular signal-regulated kinase (ERK) 1/2, and on the cell cycle status and apoptosis in the cultured MV4-11 and primary AML cells with mutant FLT-3.
RESULTS:
Treatment with LAQ824 promoted proteasomal degradation and attenuation of the levels of FLT-3 and p-FLT-3, associated with cell cycle G(1)-phase accumulation and apoptosis of MV4-11 cells. This was accompanied by attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels. STAT-5 DNA-binding activity and the levels of c-Myc and oncostatin M were also down-regulated. Cotreatment with LAQ824 and PKC412 synergistically induced apoptosis of MV4-11 cells and induced more apoptosis of the primary AML cells expressing mutant FLT-3. This was also associated with more attenuation of p-FLT-3, p-AKT, p-ERK1/2, and p-STAT5.
CONCLUSIONS:
The combination of LAQ824 and PKC412 is highly active against human AML cells with mutant FLT-3, which merits in vivo studies of the combination against human AML.
AuthorsPurva Bali, Prince George, Pamela Cohen, Jianguo Tao, Fei Guo, Celia Sigua, Anasuya Vishvanath, Anna Scuto, Srinivas Annavarapu, Warren Fiskus, Lynn Moscinski, Peter Atadja, Kapil Bhalla
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 15 Pg. 4991-7 (Aug 01 2004) ISSN: 1078-0432 [Print] United States
PMID15297399 (Publication Type: Journal Article)
Chemical References
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • LAQ824
  • Milk Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • STAT5 Transcription Factor
  • Trans-Activators
  • DNA
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Proteasome Endopeptidase Complex
  • Staurosporine
  • midostaurin
Topics
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Apoptosis
  • Blotting, Western
  • Cell Cycle
  • Cell Line, Tumor
  • DNA (chemistry)
  • DNA-Binding Proteins (metabolism)
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Synergism
  • Enzyme Inhibitors (administration & dosage)
  • Exons
  • Flow Cytometry
  • G1 Phase
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids (administration & dosage)
  • Leukemia, Myeloid, Acute (drug therapy)
  • Milk Proteins (metabolism)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Mutation
  • Phosphorylation
  • Proteasome Endopeptidase Complex (metabolism)
  • Protein Binding
  • Protein Serine-Threonine Kinases (metabolism)
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger (metabolism)
  • Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT5 Transcription Factor
  • Signal Transduction (drug effects)
  • Staurosporine (analogs & derivatives, antagonists & inhibitors)
  • Time Factors
  • Trans-Activators (metabolism)
  • fms-Like Tyrosine Kinase 3

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