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rdf:type |
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lifeskim:mentions |
umls-concept:C0031727,
umls-concept:C0162638,
umls-concept:C0521451,
umls-concept:C1143185,
umls-concept:C1150587,
umls-concept:C1366876,
umls-concept:C1367731,
umls-concept:C1417008,
umls-concept:C1704259,
umls-concept:C1705632,
umls-concept:C1705987,
umls-concept:C1833235,
umls-concept:C2349975
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pubmed:issue |
32
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pubmed:dateCreated |
2002-8-5
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pubmed:abstractText |
Bisindolylmaleimide VIII (Bis VIII) has been previously shown to enhance Fas-mediated apoptosis through a protein kinase C-independent mechanism. In the present study, we examined the effect of Bis VIII on apoptosis induced by DR5 (TRAIL-R2), using an agonistic anti-human DR5 monoclonal antibody, TRA-8. Our results demonstrated that Bis VIII was able to enhance the apoptosis-inducing activity of TRA-8 both in vitro and in vivo. The combination of TRA-8 and Bis VIII led to a synergistic and sustained activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase, which was mediated by MAPK kinase 4 and was caspase-8-dependent. The mitochondrial pathway is involved in the synergistic induction of apoptosis by Bis VIII and TRA-8. Bis VIII alone induced the loss of mitochondrial membrane potential in a caspase-independent fashion without subsequent release of cytochrome c. However, in the presence of Bis VIII, TRA-8 induced more profound loss of mitochondrial membrane potential and release of cytochrome c. These results suggest that the enhanced and persistent activation of the JNK/p38 and the decreased mitochondrial membrane potential play a crucial role in synergistic induction of the death receptor-mediated apoptosis by Bis VIII. The unique ability of Bis VIII to enhance DR5-mediated apoptosis signal transduction discloses a potential utility of this compound in combination with anti-DR5 antibody in cancer therapy.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 8,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome c Group,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/MAP2K4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Maleimides,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 8,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, TNF-Related...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Tumor Necrosis Factor,
http://linkedlifedata.com/resource/pubmed/chemical/TNFRSF10B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/bisindolylmaleimide,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
277
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
29294-303
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12034736-Apoptosis,
pubmed-meshheading:12034736-Caspase 8,
pubmed-meshheading:12034736-Caspase 9,
pubmed-meshheading:12034736-Caspases,
pubmed-meshheading:12034736-Cytochrome c Group,
pubmed-meshheading:12034736-Dose-Response Relationship, Drug,
pubmed-meshheading:12034736-Enzyme Activation,
pubmed-meshheading:12034736-Enzyme Inhibitors,
pubmed-meshheading:12034736-Humans,
pubmed-meshheading:12034736-Indoles,
pubmed-meshheading:12034736-Jurkat Cells,
pubmed-meshheading:12034736-MAP Kinase Kinase 4,
pubmed-meshheading:12034736-Maleimides,
pubmed-meshheading:12034736-Microscopy, Fluorescence,
pubmed-meshheading:12034736-Mitochondria,
pubmed-meshheading:12034736-Mitogen-Activated Protein Kinase 8,
pubmed-meshheading:12034736-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:12034736-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12034736-Receptors, TNF-Related Apoptosis-Inducing Ligand,
pubmed-meshheading:12034736-Receptors, Tumor Necrosis Factor,
pubmed-meshheading:12034736-Signal Transduction,
pubmed-meshheading:12034736-Time Factors,
pubmed-meshheading:12034736-Tumor Cells, Cultured,
pubmed-meshheading:12034736-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2002
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pubmed:articleTitle |
Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4/JNK/p38 kinase and the mitochondrial pathways.
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pubmed:affiliation |
Biomedical Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
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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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