5/8/2023 0 Comments Alexandra subler![]() These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.Įxpression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). 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. 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. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. 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. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. They also raise the possibility that this strategy may be effective in some Bcr/Abl(+) cells that are resistant to STI571 through increased Bcr/Abl expression.Įmergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. Together, these findings indicate that combined exposure of Bcr/Abl(+) cells to the kinase inhibitor STI571 and HDIs leads to diverse perturbations in signaling and cell cycle-regulatory proteins, associated with a marked increase in mitochondrial damage and cell death. ![]() Lastly, inducible expression of a constitutively active MEK1/2 construct significantly attenuated SAHA/STI571-mediated apoptosis in K562 cells, implicating disruption of the Raf/MEK/ERK axis in synergistic antileukemic effects of this drug combination. ![]() STI571 and SAHA also interacted synergistically to induce apoptosis in STI571-resistant K562 and LAMA 84 cells that display increased Bcr/Abl protein expression. Coexposure of Bcr/Abl(+) cells to STI571 also blocked SAHA-mediated induction of p21(CIP1) and resulted in down-regulation of Bcr/Abl protein expression. Coexposure of cells to HDIs in conjunction with STI571 resulted in multiple perturbations in signaling and cell cycle-regulatory proteins, including down-regulation of Raf, phospho-mitogen-activated protein kinase kinase (MEK), phospho-extracellular signal-regulated kinase (ERK), phospho-Akt, phospho-signal transducers and activators of transcription 5, cyclin D1, and Mcl-1, accompanied by dephosphorylation and cleavage of retinoblastoma protein and a striking increase in phosphorylation of c-Jun NH(2)-terminal kinase. Similar events were observed in other Bcr/Abl(+) cells (i.e., LAMA 84), and in cells exposed to STI571 in combination with the HDI sodium butyrate. Cotreatment of K562 cells with 250 nM imatinib mesylate and 2.0 micro M suberoylanilide hydroxamic acid (SAHA) for 24 h, exposures that were minimally toxic alone, resulted in a marked increase in mitochondrial damage (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), caspase activation, and apoptosis. VaynerMedia Gary Vaynerchuk Rob Lenois Nick Miaritis John Terrana Kaylen McNamara Lisa Eleanor Buckley Peter Chun Harriet Flory J.C.Interactions between the Bcr/Abl kinase inhibitor STI571 (Gleevec, imatinib mesylate) and histone deacetylase inhibitors (HDIs) have been examined in STI571-sensitive and -resistant Bcr/Abl(+) human leukemia cells (K562 and LAMA 84). ![]() Sounds simple, but it takes humility and respect. To allow the consumer to guide the way!! The practice and art of PCSing allows us to see what’s resonating and build on that momentum, crafting and shaping more culturally relevant, effective work. This commitment inspired us to introduce the role of Post Creative Strategist and for every strategist to adopt the title and the responsibilities of Post Creative Strategist (PCS).Īs Post Creative Strategists, our task is to always be actively listening to what the consumer is saying and how they are responding and reacting to all our work, across all platforms and channels, to provide a pipeline of fresh, on-going real time insights. ![]() I joined Vaynermedia 3.5 years ago for that reason, Gary Vaynerchuk‘s strong belief in always being consumer-up and consumer-led. Those who know me and have worked with me know that I have always been a very human centric strategist. ![]()
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