ArticleLeukemia2010
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.
Article in Leukemia, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia.Leukemia · 2019Article
- Epigenetic drug combination induces remission in mouse xenograft models of pediatric acute myeloid leukemia.Leukemia research · 2017Article
- Genetic regulation of the RUNX transcription factor family has antitumor effects.The Journal of clinical investigation · 2017Article
- Treatment of Relapsed/Refractory Acute Myeloid Leukemia.Current treatment options in oncology · 2017Review
- The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells.Blood cancer journal · 2017Article
- Active hexose-correlated compound enhances extrinsic-pathway-mediated apoptosis of Acute Myeloid Leukemic cells.PloS one · 2017Article
- Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2016Article
- Targeting FLT3 to treat leukemia.Expert opinion on therapeutic targets · 2015Review
- Mitochondrial Profiling of Acute Myeloid Leukemia in the Assessment of Response to Apoptosis Modulating Drugs.PloS one · 2015Article
- PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment.Journal of molecular medicine (Berlin, Germany) · 2013Article
- Targeting p53 by small molecules in hematological malignancies.Journal of hematology & oncology · 2013Review
- Review
- Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment.Cancer letters · 2013Article
- Article
- The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway.Molecular cancer therapeutics · 2011Article
- Phase I study of sorafenib in patients with refractory or relapsed acute leukemias.Haematologica · 2011Article
- Article
- Clinical proteomics of myeloid leukemia.Genome medicine · 2010Article
- p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells.International journal of hematology · 2010Article
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Authors and funding
9 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.