title: Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.
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.
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America ; Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.forename: Andreea Lucia
authors.initials: AL
authors.lastname: Stancu
authors.forename: Ioana
authors.initials: I
authors.lastname: Goganau
authors.forename: Stefana Maria
authors.initials: SM
authors.lastname: Petrescu
authors.forename: Bodvael
authors.initials: B
authors.lastname: Pennarun
authors.forename: Thierry
authors.initials: T
authors.lastname: Bertomeu
authors.forename: Rajan
authors.initials: R
authors.lastname: Dewar
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects*; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011621:Pteridines; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C518477:BI 2536; D001549:Benzamides; D001897:Boronic Acids; D006574:Heterocyclic Compounds, 2-Ring; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D011719:Pyrazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C498826:nilotinib; D017239:Paclitaxel; D000069439:Dasatinib