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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0013126,
umls-concept:C0040077,
umls-concept:C0042338,
umls-concept:C0085828,
umls-concept:C0162508,
umls-concept:C0162638,
umls-concept:C0163272,
umls-concept:C0205263,
umls-concept:C0253023,
umls-concept:C0667830,
umls-concept:C1879547
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pubmed:issue |
2
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pubmed:dateCreated |
2003-1-15
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pubmed:abstractText |
The molecular mode of cell killing by the antiviral drug (E)-5-(2-bromovinyl-2'-deoxyuridine (BVDU) was studied in Chinese hamster ovary (CHO) cells stably transfected with the thymidine kinase gene (tk) of varicella zoster virus (CHO-VZVtk). The colony-forming ability of the cells was reduced to <1% at a concentration of approximately 1 microM BVDU, whereas for nontransfected cells or cells transfected with tk gene of herpes simplex virus type 1 (CHO-HSVtk), a 1000-fold higher dose was required to achieve the same response. BVDU inhibited thymidylate synthase in CHO-VZVtk but not in CHO-HSVtk and control cells. On the other hand, the drug was incorporated into DNA of VZVtk- and HSVtk-expressing cells to nearly equal amounts. Because coexposure of CHO-VZVtk cells to exogenous thymidine protected them from BVDU-induced cell killing, the cells obviously die because of thymidine depletion. At highly cytotoxic BVDU doses (50 microM) and longer exposure times (24-48 h), VZVtk cells were blocked to some extent in S and G2/M phase and underwent apoptosis (48-72 h). Not only apoptosis but also necrosis was induced. The findings also show that the drug causes the induction of c-Jun and the activation of activator protein-1 resulting in increased level of Fas ligand (FasL) and caspase-8/-3 activation. Bid and poly(ADP-ribose) polymerase were cleaved by caspases. Expression of Bax increased, whereas Bcl-2/Bcl-x(L) remained unchanged. Transfection of dominant-negative Fas-associated death domain and inhibition of caspase-8 by N-benzyloxycarbonyl-IETD-fluoromethyl ketone strongly abrogated BVDU-induced apoptosis, indicating Fas/FasL to be crucially involved. Thus, BVDU-triggered apoptosis differs significantly from that induced by ganciclovir, which induces in the same cellular background the mitochondrial damage pathway.
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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/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Bromodeoxyuridine,
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
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/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/FADD protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/FASLG protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Fas Ligand Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Fas-Associated Death Domain Protein,
http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein...,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor AP-1,
http://linkedlifedata.com/resource/pubmed/chemical/brivudine
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0026-895X
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
63
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
439-49
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12527816-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:12527816-Animals,
pubmed-meshheading:12527816-Antiviral Agents,
pubmed-meshheading:12527816-Apoptosis,
pubmed-meshheading:12527816-Bromodeoxyuridine,
pubmed-meshheading:12527816-CHO Cells,
pubmed-meshheading:12527816-Carrier Proteins,
pubmed-meshheading:12527816-Caspase 8,
pubmed-meshheading:12527816-Caspase 9,
pubmed-meshheading:12527816-Caspases,
pubmed-meshheading:12527816-Cell Cycle,
pubmed-meshheading:12527816-Cricetinae,
pubmed-meshheading:12527816-DNA,
pubmed-meshheading:12527816-Fas Ligand Protein,
pubmed-meshheading:12527816-Fas-Associated Death Domain Protein,
pubmed-meshheading:12527816-Genome,
pubmed-meshheading:12527816-Herpesvirus 3, Human,
pubmed-meshheading:12527816-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:12527816-Membrane Glycoproteins,
pubmed-meshheading:12527816-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12527816-Necrosis,
pubmed-meshheading:12527816-Simplexvirus,
pubmed-meshheading:12527816-Thymidine Kinase,
pubmed-meshheading:12527816-Thymidylate Synthase,
pubmed-meshheading:12527816-Transcription Factor AP-1,
pubmed-meshheading:12527816-Transfection
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pubmed:year |
2003
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pubmed:articleTitle |
Apoptosis induced by (E)-5-(2-bromovinyl)-2'-deoxyuridine in varicella zoster virus thymidine kinase-expressing cells is driven by activation of c-Jun/activator protein-1 and Fas ligand/caspase-8.
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pubmed:affiliation |
Institute of Toxicology, Medical Faculty, University of Mainz, Mainz, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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