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- Title
Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis.
- Authors
Kojima, K.; Konopleva, M.; Tsao, T.; Andreeff, M.; Ishida, H.; Shiotsu, Y.; Jin, L.; Tabe, Y.; Nakakuma, H.
- Abstract
Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.
- Subjects
LEUKEMIA treatment; PROTEIN-tyrosine kinases; CELL-mediated cytotoxicity; APOPTOSIS; DRUG therapy; CELL death; PROTEIN metabolism; CELL lines; CELL physiology; COMPARATIVE studies; DOXORUBICIN; HETEROCYCLIC compounds; IMIDAZOLES; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; PROTEINS; PROTEOLYTIC enzymes; PYRIDINE; RESEARCH; TRANSFERASES; EVALUATION research; ACUTE myeloid leukemia; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Leukemia (08876924), 2010, Vol 24, Issue 1, p33
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/leu.2009.212