Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Mitochondrial Dysfunction and Apoptosis Induced by 7-Hydroxystaurosporine and Mitogen-Activated Protein Kinase Kinase Inhibitors in Human Leukemia Cells That Ectopically Express Bcl-2 and Bcl-xL

2003 ◽  
Vol 64 (6) ◽  
pp. 1402-1409 ◽  
Author(s):  
Yun Dai ◽  
Paul Dent ◽  
Steven Grant
Keyword(s):  
Protein Kinase ◽  
Tumor Necrosis ◽  
Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Human Leukemia Cells ◽  
Mitogen Activated Protein ◽  
Necrosis Factor ◽  
Protein Kinase Kinase

Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 509-518 ◽  
Author(s):  
Yun Dai ◽  
Mohamed Rahmani ◽  
Xin-Yan Pei ◽  
Paul Dent ◽  
Steven Grant
Keyword(s):  
Protein Kinase ◽  
Imatinib Mesylate ◽  
Myelogenous Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

Abstract Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl+ human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor κB (NF-κB)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-β-d-ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl- human leukemia cells. Collectively, these findings suggest that a strategy combining flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies. (Blood. 2004;104:509-518)

Sign in / Sign up

Export Citation Format

Share Document