ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells
| Autor: | Ivan F. Loncarevic, Frank-D. Böhmer, Sebastian Scholl, K. Höffken, Joachim H. Clement, R. Müller |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Indoles Myeloid Retinoic acid Apoptosis Tretinoin Biology chemistry.chemical_compound fluids and secretions Cell Line Tumor hemic and lymphatic diseases Granulocyte Colony-Stimulating Factor Survivin medicine Humans Protein Kinase Inhibitors Wild type Myeloid leukemia Cell Differentiation hemic and immune systems Hematology Enzyme Activation medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 fms-Like Tyrosine Kinase 3 Oncology chemistry Cell culture Mutation embryonic structures Cancer research Tyrosine kinase |
| Zdroj: | Leukemia Research. 30:633-642 |
| ISSN: | 0145-2126 |
| DOI: | 10.1016/j.leukres.2005.10.005 |
| Popis: | Among activating Flt3 mutations that have been shown in 25–30% of acute myeloid leukaemia (AML) Flt3-internal tandem duplication (ITD) mutations are predominant. We investigated the influence of all- trans -retinoic acid (ATRA) and granulocyte colony stimulating factor (G-CSF) for their effects on differentiation and apoptosis in human cell lines with different Flt3 variants (THP-1 versus MV4-11 and MOLM13) dependent on the inhibition of Flt3 tyrosine kinase by the bis(lH-2-indolyl)methanone D-65476. While myeloid differentiation was not observed in both Flt3-ITD cell lines (MV4-11 and MOLM13), we demonstrate an enhanced proapoptotic effect of D-65476 in the presence of ATRA that was restricted to the Flt3-ITD expressing cells. The combined treatment with ATRA and D-65476 also led to a pronounced down-regulation of surviv in on mRNA and protein level in Flt3-ITD but not in Flt3 wildtype expressing cells (THP-1). Surprisingly, there was no differential expression of important proteins like Bcl-X L , Bcl-2 or Bax that might explain enhanced apoptosis. Furthermore, Akt phosphorylation after stimulation with Flt3 ligand dependent on D-65476 was not affected by pretreatment with ATRA. We suggest that regulation of inhibitors of apoptosis might play a crucial role how ATRA can increase the proapoptotic effect of Flt3 inhibitors in myeloid leukemia cells expressing Flt3-ITD. This effect can potentially be exploited for the treatment of Flt3-ITD positive acute myeloid leukemia. |
| Databáze: | OpenAIRE |
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