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

• 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
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.6.6.4101

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.