Source:http://linkedlifedata.com/resource/pubmed/id/14645670
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0017262,
umls-concept:C0023418,
umls-concept:C0023688,
umls-concept:C0033414,
umls-concept:C0077681,
umls-concept:C0086418,
umls-concept:C0162638,
umls-concept:C0205263,
umls-concept:C0277785,
umls-concept:C0333516,
umls-concept:C0376515,
umls-concept:C0385242,
umls-concept:C0521451,
umls-concept:C1171362,
umls-concept:C1332397,
umls-concept:C1336646,
umls-concept:C1515670,
umls-concept:C2347168
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| pubmed:issue |
6
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| pubmed:dateCreated |
2003-12-3
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| pubmed:abstractText |
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-alpha 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.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/7-hydroxystaurosporine,
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/BCL2L1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Staurosporine,
http://linkedlifedata.com/resource/pubmed/chemical/TNF-Related Apoptosis-Inducing...,
http://linkedlifedata.com/resource/pubmed/chemical/TNFSF10 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
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| pubmed:issn |
0026-895X
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
64
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1402-9
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:14645670-Apoptosis,
pubmed-meshheading:14645670-Apoptosis Regulatory Proteins,
pubmed-meshheading:14645670-Enzyme Inhibitors,
pubmed-meshheading:14645670-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:14645670-Humans,
pubmed-meshheading:14645670-Ligands,
pubmed-meshheading:14645670-Membrane Glycoproteins,
pubmed-meshheading:14645670-Mitochondria,
pubmed-meshheading:14645670-Mitochondrial Diseases,
pubmed-meshheading:14645670-Mitogen-Activated Protein Kinases,
pubmed-meshheading:14645670-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:14645670-Staurosporine,
pubmed-meshheading:14645670-TNF-Related Apoptosis-Inducing Ligand,
pubmed-meshheading:14645670-Tumor Necrosis Factor-alpha,
pubmed-meshheading:14645670-U937 Cells,
pubmed-meshheading:14645670-bcl-X Protein
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| pubmed:year |
2003
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| pubmed:articleTitle |
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.
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| pubmed:affiliation |
Division of Hematology/Oncology, Medical College of Virginia/Virginia Commonwealth University, MCV Station Box 230, Richmond, VA 23298, USA. stgrant@hsc.vcu.edu
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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