A new nonpeptidic inhibitor of 14-3-3 induces apoptotic cell death in chronic myeloid leukemia sensitive or resistant to imatinib.
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.
Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, Policlinico S. Orsola, Bologna, Italy.
Manuela
M
Mancini
Valentina
V
Corradi
Sara
S
Petta
Enza
E
Barbieri
Fabrizio
F
Manetti
Maurizio
M
Botta
Maria Alessandra
MA
Santucci
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; C557642:BV02 compound; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D000068877:Imatinib Mesylate