Imatinib and Nilotinib induce apoptosis of chronic myeloid leukemia cells through a Bim-dependant pathway modulated by cytokines

It is an important challenge to better understand the mechanisms of tyrosine kinase inhibitors-induced apoptosis in CML cells. Thus, we have investigated how this apoptosis can be modulated by extracellular factors. Apoptosis induced by imatinib and nilotinib was determined in BCR-ABL expressing cel...

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Bibliographic Details
Published in:Cancer biology & therapy 2007-06, Vol.6 (6), p.912-919
Main Authors: Belloc, Francis, Moreau-Gaudry, François, Uhalde, Maialen, Cazalis, Laurie, Jeanneteau, Marie, Lacombe, Francis, Praloran, Vincent, Mahon, François-Xavier
Format: Article
Language:English
Subjects:
Animals
Antigens, CD34 - biosynthesis
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis Regulatory Proteins - metabolism
Bcl-2-Like Protein 11
Benzamides
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Line, Tumor
Cycle
Cytokines - metabolism
Gene Expression Regulation, Leukemic
Humans
Imatinib Mesylate
K562 Cells
Landes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Membrane Proteins - metabolism
Mice
Models, Biological
Organogenesis
Piperazines - pharmacology
Proteins
Proto-Oncogene Proteins - metabolism
Pyrimidines - pharmacology
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Summary:It is an important challenge to better understand the mechanisms of tyrosine kinase inhibitors-induced apoptosis in CML cells. Thus, we have investigated how this apoptosis can be modulated by extracellular factors. Apoptosis induced by imatinib and nilotinib was determined in BCR-ABL expressing cell lines and primary CML CD34+ cells. Both molecules induced apoptosis of BCR-ABL expressing cells. This apoptosis was inhibited by protein synthesis inhibition in both K562 and CML CD34+ cells. In K562, 80% inhibition of the BCR-ABL auto-phosphorylation by either imatinib or nilotinib induced a two fold increase in Bim-EL expression and induction of apoptosis in 48h. Bim accumulation preceded apoptosis induction and was completely abolished by depletion in Bim using shRNA. However, the anti-proliferative effect of imatinib was preserved in Bim-depleted cells. When K562 cells were cultured in a cytokine containing medium, the pro-apoptotic effect of nilotinib was decreased by 68% and this was related to a decrease in Bim-EL de-phosphorylation and accumulation. Similarly, the presence of a combination of cytokines inhibited 88% of NIL- and 39% of IMA-induced apoptosis in primary CML CD34+ cells. In conclusion, both nilotinib and imatinib induce apoptosis through Bim accumulation independently of cell cycle arrest. However, the pro-apoptotic effect of both molecules can be attenuated by the presence of cytokines and growth factors, particularly concerning nilotinib. Thus BCR-ABL inhibition restores the cytokine dependence but is not sufficient to induce apoptosis when other signaling pathways are activated.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.6.6.4101