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

Abstract

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

Inhibitors of Apoptosis Proteins in Injury and Disease

“…cIAP-2 overexpression has been noted in Hodgkin's disease (22) and bronchopulmonary dysplasia (23). The cIAP-1 gene appears to be amplified and overexpressed in esophageal squamous cell carcinoma (24) and various forms of leukemia (25)(26)(27). In addition, ML-IAP has been shown to be overexpressed in human melanoma and melanoma cell lines (2).…”

“…Apollon may play a role in glial cell tumorogenesis and is expressed in some ovarian cancer cell lines (10). Dysregulation of XIAP has not been definitely reported in human diseases, but overexpression has been reported in leukemias (25)(26)(27), and underexpression has been implicated in androgenetic alopecia where levels may be influenced by finasteride treatment (28). Taken together, the available data strongly indicate that IAPs are critically involved in the oncogenic process.…”

Role of Chk1 and Chk2 in Ara‐C‐induced differentiation of human leukemia K562 cells

“…The chronic myelogenous leukemia cell line K562 is induced in vitro to undergo erythroid differentiation by a variety of compounds, among them Ara-C (Fang et al . 2000;Huang et al .…”

Imatinib mesylate‐resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol

“…Imatinib mesylate (Gleevec), also known as STI571, targets the ATP-binding site of different tyrosine kinases, including BCR-ABL, the platelet-derived growth factor (PDGF) receptor (9), and c-Kit (10). Imatinib selectively induces the growth arrest and the apoptosis of BCR-ABL-positive leukemia cells with a minimal effect on normal hematopoietic progenitors (11)(12). Of note, this agent has proven very effective with patients in the chronic phase of CML (13) and to a lesser extent in accelerated phase and blast crisis (14).…”