Abstract Bcr-Abl fusion protein plays a critical role in the pathogenesis and progression of Chronic Myelogenous Leukemia (CML) and in some of the Acute Lymphocytic Leukemia (ALL) cases. Current inhibitors of Abl kinases, such as Imatinib, have shown great promise in the treatment of CML, however, the emergence of the resistance and the persistence of the residual disease have underlined the importance of finding new ways of treatment CML and especially of the resistant forms of CML. We and others have previously shown that Bortezomib (FDA approved for the treatment of Multiple Myeloma), a selective proteasome inhibitor, efficiently induces apoptosis in Imatinib resistant Bcr-Abl T315I cells, and established Bortezomib as a potential important treatment in Bcr-Abl positive leukemias, determining the initiation of at least five different clinical trials for the treatment of CML, alone or in combination. We are further showing here that Bortezomib in combination with the mitotic inhibitor Paclitaxel act synergistically in inducing apoptosis in Bcr-Abl positive cells. Paclitaxel, a mitotic inhibitor drug (FDA approved drug for the treatment of lung, ovarian, breast, head and neck cancers, and advanced forms of Kaposi's sarcoma) is also now in clinical trials for the treatment of CML. However, to our knowledge, there are no clinical trials or other studies regarding the combined treatment of Bortezomib and Paclitaxel in Bcr-Abl positive CML. RESULTS: Combined treatment of Bortezomib and Paclitaxel synergistically induces cell death in human Bcr-Abl positive K562 cell line, by activating the initiator caspase 9 and effector caspase 3, which leads to the cleavage of a number of substrates, such as Poly ADP Ribose Polymerase (PARP), and results in apoptosis. Additionally, the exposure of the Bcr-Abl positive leukemia cells to the Bortezomib/Paclitaxel regimen results in an increase in the activation of the stress-related MAP kinases (such as p38 MAPK and JNK) versus the cytoprotective kinases (ERK1, ERK2), suggesting a possible implication of JNK and p38 MAPK in mediating the effect of the combined treatment. Moreover, we also show that the combined treatment is effective in inducing apoptosis in the murine Baf3 Bcr-Abl and Imatinib resistant Baf3 Bcr-Abl T315I cell lines, suggesting a potential use of the regimen in Imatinib resistant forms of CML. CONCLUSION: Taken together, these findings underline that the combined treatment with Bortezomib and Paclitaxel represents a potentially promising strategy for the treatment of Chronic Myelogenous Leukemia in general, and of Imatinib resistant CML in particular. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 205.
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