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Molecular Pharmacology

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Research ArticleArticle

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

Yun Dai, Paul Dent and Steven Grant
Molecular Pharmacology December 2003, 64 (6) 1402-1409; DOI: https://doi.org/10.1124/mol.64.6.1402
Yun Dai
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Paul Dent
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Steven Grant
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Abstract

Previous studies have demonstrated that cotreatment with mitogen activated-protein kinase kinase (MEK) 1/2 inhibitors (e.g., PD184352) and the checkpoint abrogator 7-hydroxystaurosporine (UCN-01) dramatically induces apoptosis in a variety of human leukemia and multiple myeloma cell types. The purpose of this study was to evaluate the roles of Bcl-2 family members and the relative contribution of the intrinsic mitochondrial versus the extrinsic receptor-related apoptotic pathways to MEK inhibitors/UCN-01-induced leukemic cell death. Cotreatment of U937 cells with PD184352 and UCN-01 resulted in the activation of procaspase-3, -9, and -8 as well as Bid cleavage. PD184352/UCN-01-induced mitochondrial dysfunction and apoptosis were both substantially attenuated in cells ectopically expressing Bcl-2, an N-terminal phosphorylation loop-deleted mutant Bcl-2, or Bcl-xL, but not in cells expressing dominant-negative (DN) caspase-8, cytokine response modifier A (cowpox virus-encoded antiapoptotic protein), or DN Fas-associated death domain. Coadministration of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or TNF-α substantially increased MEK inhibitors (e.g., PD184352 or U0126)/UCN-01-induced mitochondrial dysfunction, activation of procaspase-8 and Bid, and apoptosis in Bcl-2- and Bcl-xL-overexpressing cells but not in those in which the extrinsic pathway was interrupted. Together, these findings suggest that the MEK inhibitors/UCN-01 regimen primarily induces leukemic cell apoptosis by engaging the intrinsic, mitochondrial apoptotic pathway and that resistance to these events conferred by increased expression of certain antiapoptotic Bcl-2 family members can be overcome, at least in part, by coadministration of TRAIL and other agents that activate the extrinsic apoptotic cascade.

  • Received June 17, 2003.
  • Accepted September 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (6)
Molecular Pharmacology
Vol. 64, Issue 6
1 Dec 2003
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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…
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Research ArticleArticle

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

Yun Dai, Paul Dent and Steven Grant
Molecular Pharmacology December 1, 2003, 64 (6) 1402-1409; DOI: https://doi.org/10.1124/mol.64.6.1402

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Research ArticleArticle

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

Yun Dai, Paul Dent and Steven Grant
Molecular Pharmacology December 1, 2003, 64 (6) 1402-1409; DOI: https://doi.org/10.1124/mol.64.6.1402
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