CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs

摘要: The differentiation and apoptosis-sensitizing effects of the Bcr-Abl-specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl-positive HL-60/Bcr-Abl K562 cells. First, results demonstrate that ectopic expression p185 Bcr-Abl fusion protein induced hemoglobin acute myeloid leukemia (AML) HL-60 Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased levels chronic (CML) blast crisis cells, which express p210 protein. As compared with HL-60/neo, cells resistant apoptosis by Ara-C, doxorubicin, or tumor necrosis factor-alpha (TNF-alpha), was associated reduced processing caspase-8 Bid decreased cytosolic accumulation cytochrome c (cyt c). CGP57148B alone CD11b treatment down-regulated antiapoptotic XIAP, cIAP1, Bcl-x(L), without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), ligand, Abl, levels. inhibited constitutively active Akt NFkappaB Attenuation activity transdominant repressor IkappaB sensitized TNF-alpha but not Ara-C doxorubicin. Importantly, cotreatment significantly Ara-C- doxorubicin-induced This greater cyt PARP cleavage caspase-3. These vitro data indicate combinations antileukemic drugs such may have improved vivo efficacy against leukemia.