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

被引:86
作者
Dai, Y
Rahmani, M
Pei, XY
Dent, P
Grant, S
机构
[1] Virginia Commonwealth Univ, Med Coll Virginia, Dept Med, Div Hematol Oncol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Med Coll Virginia, Dept Biochem, Richmond, VA 23298 USA
[3] Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol, Richmond, VA 23298 USA
关键词
D O I
10.1182/blood-2003-12-4121
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 kappaB (NF-kappaB)/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, Hick, 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 pro- mote bortezomib-mediated Bcr/Abl downregulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-beta-D-ribofuranosylbenzinidasole). Finally, the bortezomlb/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. (C) 2004 by The American Society of Hematology.
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页码:509 / 518
页数:10
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