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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0010749,
umls-concept:C0017638,
umls-concept:C0030685,
umls-concept:C0086418,
umls-concept:C0162638,
umls-concept:C0279023,
umls-concept:C0385242,
umls-concept:C0391871,
umls-concept:C0680255,
umls-concept:C1283071,
umls-concept:C1314939,
umls-concept:C1336646,
umls-concept:C1963578,
umls-concept:C2349975
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pubmed:issue |
31
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pubmed:dateCreated |
2001-7-20
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pubmed:abstractText |
Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms.
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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/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
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/Lomustine,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
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/Tumor Suppressor Protein p53
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0950-9232
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
20
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4128-37
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11464279-Antineoplastic Agents, Alkylating,
pubmed-meshheading:11464279-Apoptosis,
pubmed-meshheading:11464279-Apoptosis Regulatory Proteins,
pubmed-meshheading:11464279-Blotting, Western,
pubmed-meshheading:11464279-Brain Neoplasms,
pubmed-meshheading:11464279-Caspase 8,
pubmed-meshheading:11464279-Caspase 9,
pubmed-meshheading:11464279-Caspases,
pubmed-meshheading:11464279-Cytochrome c Group,
pubmed-meshheading:11464279-Flow Cytometry,
pubmed-meshheading:11464279-Glioma,
pubmed-meshheading:11464279-Humans,
pubmed-meshheading:11464279-Lomustine,
pubmed-meshheading:11464279-Membrane Glycoproteins,
pubmed-meshheading:11464279-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:11464279-TNF-Related Apoptosis-Inducing Ligand,
pubmed-meshheading:11464279-Tumor Cells, Cultured,
pubmed-meshheading:11464279-Tumor Necrosis Factor-alpha,
pubmed-meshheading:11464279-Tumor Suppressor Protein p53
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pubmed:year |
2001
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pubmed:articleTitle |
CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release.
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pubmed:affiliation |
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Medical School, Tübingen, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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