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

The differentiation and apoptosis-sensitizing effects of the Bcr-Abl-specif ic tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determi ned in human Bcr-Abl-positive HL-60/Bcr-Abl and K562 cells. First, the resu lts demonstrate that the ectopic expression of the p185 Bcr-Abl fusion prot ein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exp osure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglo bin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared wit h HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induc ed by Ara-C, doxorubicin, or tumor necrosis factor-alpha (TNF-alpha), which was associated with reduced processing of caspase-8 and Bid protein and de creased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP5714 8B alone increased hemoglobin levels and CD11b expression and induced apopt osis of HL60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated ant iapoptotic XIAP, cIAP1, and Bcl-x(L), without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active AM kinase and NF kappa B in Bcr-Abl-positive cells. A ttenuation of NF kappa B activity by ectopic expression of transdominant re pressor of I kappa B sensitized HL-60/Bcr-Abl and K562 cells to TNF-alpha b ut not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatme nt with CGP57148B significantly increased Ara-C- or doxorubicin-induced apo ptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cy tosolic accumulation of cyt c and PARP cleavage activity of caspase-3. Thes e in vitro data indicate that combinations of CGP57148B and antileukemic dr ugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl-positi ve acute leukemia. (Blood. 2000;96:2246-2253) (C) 2000 by The American Soci ety of Hematology.