Abstract
Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.
Highlights
The t(9:22) chromosomal translocation resulting in the Philadelphia chromosome leads to the expression of the BcrAbl fusion protein, which plays a critical role in the pathogenesis and progression of Chronic Myeloid Leukemia (CML), in a subset of Acute Lymphoblastic Leukemia (Ph+ALL; 15% to 30% cases) and occasionally in Acute Myelogenous Leukemia (Ph+AML) [1]
In order to evaluate if the combined bortezomib/paclitaxel regimen can efficiently shut down Bcr-Abl and induce cell death in Bcr-Abl-positive leukemic cell lines that are resistant to imatinib, we developed two different cell lines derived from K562 (K562-R) and LAMA84 (LAMA84-R) cell lines, which are resistant to 1μM imatinib
Our findings indicate that the bortezomib in combination with four different mitotic inhibitors, that repress mitosis by different mechanisms [23,24,25] are able to shut down Bcr-Abl activity and result in caspase-dependent cell death in Tyrosine-Kinase Inhibitors (TKIs)-resistant and -sensitive Bcr-Abl-positive cell lines
Summary
The t(9:22) chromosomal translocation resulting in the Philadelphia chromosome leads to the expression of the BcrAbl fusion protein, which plays a critical role in the pathogenesis and progression of Chronic Myeloid Leukemia (CML), in a subset of Acute Lymphoblastic Leukemia (Ph+ALL; 15% to 30% cases) and occasionally in Acute Myelogenous Leukemia (Ph+AML) [1]. Current inhibitors of Abl kinases, such as imatinib mesylate (imatinib), dasatinib or nilotinib have shown great potential in the treatment of CML. The emergence of resistance and residual disease eventually lead to CML progression [3]. Dasatinib or nilotinib resistance may emerge through Bcr-Abl mutations (such as T315I) and/or Bcr-Abl amplification [4]. Novel therapeutic strategies that target both imatinib-, dasatinib- or nilotinibresistant and -sensitive Bcr-Abl-positive leukemias, such as CML, need to be developed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
