Resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitor imatinib mesylate (IM) is most often due to point mutations in the Bcr-Abl fusion gene. T315I mutation (resulting in substitution of Ile for a Thr residue at the "gatekeeper" position 315) raises particular concern, because it also provides resistance to second-generation kinase inhibitors already approved for clinical use (nilotinib and dasatinib). Much effort is therefore focused on alternative molecular-based strategies. Previous studies proved that binding to 14-3-3 scaffolding proteins leads to cytoplasmic compartmentalization and suppression of proapoptotic and antiproliferative signals associated with Bcr-Abl protein kinase, hence contributing to leukemic clone expansion. Here we investigated the effect of 14-3-3 inhibition disruption on hematopoietic cells expressing the IM-sensitive wild type Bcr-Abl and the IM-resistant T315I mutation. Using a virtual screening protocol and docking simulations, we identified a nonpeptidic inhibitor of 14-3-3, named BV02, that exhibits a remarkable cytotoxicity against both cell types. c-Abl release from 14-3-3σ, promoting its relocation to nuclear compartment (where it triggers transcription of p73-dependent proapoptotic genes) and to mitochondrial membranes (where it induces the loss of mitochondrial transmembrane potential) combined with c-Abl enhanced association with caspase 9 (a critical step of sequential caspase activation further contributing to c-Abl pro-apoptotic function) has a prominent role in the effect of BV02 on Bcr-Abl-expressing cells. In conclusion, BV02 may be considered as a treatment option for CML and, in particular, for more advanced phases of the disease that developed IM resistance as a consequence of Bcr-Abl point mutations.
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|Titolo:||A new non-peptidic inhibitor of 14-3-3 induces apoptotic cell death in chronic myeloid leukemia sensitive or resistant to imatinib.|
|Rivista:||JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS|
|Citazione:||M., M., V., C., S., P., E., B., Manetti, F., Botta, M., et al. (2011). A new non-peptidic inhibitor of 14-3-3 induces apoptotic cell death in chronic myeloid leukemia sensitive or resistant to imatinib. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 336, 596-604.|
|Appare nelle tipologie:||1.1 Articolo in rivista|