Abstract | PURPOSE: 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.
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Authors | Purva 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 |
Journal | Clinical 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 |
PMID | 15297399
(Publication Type: Journal Article)
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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
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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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