The Multikinase Inhibitor Sorafenib Induces Apoptosis in Highly Imatinib Mesylate-Resistant Bcr/Abl+Human Leukemia Cells in Association with Signal Transducer and Activator of Transcription 5 Inhibition and Myeloid Cell Leukemia-1 Down-Regulation

2007 ◽  
Vol 72 (3) ◽  
pp. 788-795 ◽  
Author(s):  
Mohamed Rahmani ◽  
Tri K. Nguyen ◽  
Paul Dent ◽  
Steven Grant
Keyword(s):  
Imatinib Mesylate ◽  
Myeloid Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Signal Transducer ◽  
Cell Leukemia ◽  
Down Regulation ◽  
Multikinase Inhibitor ◽  
Human Leukemia Cells

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)

Arsenic Trioxide Induces Erythroid Differentiation and Apoptosis of K562 Human Leukemia Cells through the Down-Regulation of Bcl-2

2005 ◽  
Vol 40 (2) ◽  
pp. 93
Author(s):  
Yong-Kyu You ◽  
Hee-Jeong Cheong ◽  
Jong-Ho Won ◽  
Sook-Ja Kim ◽  
Sang-Byung Bae ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Erythroid Differentiation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells

scholarly journals Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation

2005 ◽  
Vol 280 (42) ◽  
pp. 35217-35227 ◽  
Author(s):  
Mohamed Rahmani ◽  
Eric Maynard Davis ◽  
Cheryl Bauer ◽  
Paul Dent ◽  
Steven Grant
Keyword(s):  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells

Highly Synergistic Interaction between Farnesyltransferase Inhibitors and the Chk1 Inhibitor UCN-01 to Induce Apoptosis in Human Leukemia Cells through Interruption of Both Akt and MEK/ERK Pathways and Activation of SEK1/JNK.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3403-3403
Author(s):  
Yun Dai ◽  
Mohamed Rahmani ◽  
Xin-Yan Pei ◽  
Payal Khanna ◽  
Paul Dent ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Farnesyltransferase Inhibitors ◽  
Down Regulation ◽  
Human Leukemia Cells ◽  
Chk1 Inhibitor ◽  
Constitutively Active

Abstract Ras mutations, which result in constitutive Ras activation, occur frequently in human malignancies, including leukemia. This finding has prompted the development of farnesyltransferase inhibitors (FTIs), which interfere with Ras farnesylation and membrane translocation necessary for Ras function. However, FTIs alone have not yet fulfilled their clinical potential, raising the possibility that their role may lie in combination with other agents. The present studies examined interactions between the farnesyltransferase inhibitor L744832 and the Chk1 inhibitor UCN-01 in human leukemia cells. Combined exposure of U937 cells to sub-toxic concentrations of UCN-01 (100nM) and the FTI L744352 (10μM) resulted in a dramatic and highly synergistic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary AML blasts, and with other farnesyltransferase inhibitors (e.g., FTI-277). These events were accompanied by cleavage of the anti-apoptotic proteins Bcl-2, XIAP, and Mcl-1. Co-administration of L744832 blocked UCN-01-mediated phosphorylation of MEK/ERK, leading to down-regulation of phospho-CREB and -p90RSK, and activation of p34cdc2 and SEK/JNK. Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -GSK, -p70S6K, -mTOR, -FKHR, -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis, but did not prevent activation of p34cdc2 and JNK, or inactivation of MEK/ERK and Akt. Enforced expression of myristolated Akt but not constitutively-active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with constitutively active Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01, and in so doing, dramatically increase mitochondria-dependent apoptosis. They also raise the possibility that combined treatment with FTIs and UCN-01 may represent a novel therapeutic strategy in leukemia.

Embelin induces apoptosis through down-regulation of XIAP in human leukemia cells

2010 ◽  
Vol 28 (4) ◽  
pp. 1584-1588 ◽  
Author(s):  
Rong Hu ◽  
Ke Zhu ◽  
Yingchun Li ◽  
Kun Yao ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells
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