AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells
| Autor: | N Gonthier, P Lagadec, Michel Dreano, J F Peyron, Véronique Imbert, Patrice Dubreuil, Emmanuel Griessinger, A Romanelli |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research Programmed cell death Myeloid bcl-X Protein Biology Cell Line Mice hemic and lymphatic diseases medicine Animals Humans Annexin A5 Child Protein Kinase Inhibitors Cell Proliferation Caspase 3 Kinase NF-kappa B Myeloid leukemia Hematology medicine.disease I-kappa B Kinase Leukemia Myeloid Acute Leukemia Haematopoiesis Pyrimidines medicine.anatomical_structure fms-Like Tyrosine Kinase 3 Oncology embryonic structures Fms-Like Tyrosine Kinase 3 Cancer research Poly(ADP-ribose) Polymerases Signal transduction |
| Zdroj: | Leukemia. 21:877-885 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/sj.leu.2404614 |
| Popis: | Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-kappaB) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-kappaB. Pharmacological inhibition of either FLT3 with AG1296 or NF-kappaB with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML. |
| Databáze: | OpenAIRE |
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