期刊
BMC CANCER
卷 9, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1471-2407-9-53
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资金
- German Federal Ministry for Instruction and Research (BMBF) trough the National Genom Research Network [01 GS 0104]
- Deutsche Forschungsgemeinschaft [DFG-RU 728/3-1]
- Alfred und Angelika Gutermuth Foundation, Deutsche Krebshilfe e. V. [DKH-107063, DKH-107741]
- Deutsche Jose Carreras Leukamie-Stiftung e. V. [DJCLS - R 07/27f]
Background: Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, is efficacious in treating chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL). However, most advanced-phase CML and Ph+ ALL patients relapse on Imatinib therapy. Several mechanisms of refractoriness have been reported, including the activation of the Src-family kinases (SFK). Here, we investigated the biological effect of the new specific dual Src/Abl kinase inhibitor AZD0530 on Ph+ leukaemic cells. Methods: Cell lines used included BV173 (CML in myeloid blast crisis), SEM t(4; 11), Ba/F3 (IL-3 dependent murine pro B), p185(Bcr-Abl) infected Ba/F3 cells, p185(Bcr-Abl) mutant infected Ba/F3 cells, SupB15 (Ph+ ALL) and Imatinib resistant SupB15 (RTSupB15) (Ph+ ALL) cells. Cells were exposed to AZD0530 and Imatinib. Cell proliferation, apoptosis, survival and signalling pathways were assessed by dye exclusion, flow cytometry and Western blotting respectively. Results: AZD0530 specifically inhibited the growth of, and induced apoptosis in CML and Ph+ ALL cells in a dose dependent manner, but showed only marginal effects on Ph- ALL cells. Resistance to Imatinib due to the mutation Y253F in p185(Bcr-Abl) was overcome by AZD0530. Combination of AZD0530 and Imatinib showed an additive inhibitory effect on the proliferation of CML BV173 cells but not on Ph+ ALL SupB15 cells. An ongoing transphosphorylation was demonstrated between SFKs and Bcr-Abl. AZD0530 significantly down-regulated the activation of survival signalling pathways in Ph+ cells, resistant or sensitive to Imatinib, with the exception of the RTSupB15. Conclusion: Our results indicate that AZD0530 targets both Src and Bcr-Abl kinase activity and reduces the leukaemic maintenance by Bcr-Abl.
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