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Molecular Pharmacology

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Research ArticleArticle

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

Maja T. Tomicic, Claudia Friedrichs, Markus Christmann, Peter Wutzler, Rudolf Thust and Bernd Kaina
Molecular Pharmacology February 2003, 63 (2) 439-449; DOI: https://doi.org/10.1124/mol.63.2.439
Maja T. Tomicic
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Claudia Friedrichs
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Markus Christmann
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Peter Wutzler
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Rudolf Thust
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Bernd Kaina
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Abstract

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 ∼1 μM 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 μM) 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-xL 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.

Footnotes

  • The work was supported by Deutsche Forschungsgemeinschaft Grants KA 724/7-3 and 7-4 (to B.K.) and TH 670/1-3 (to R.T.).

  • Abbreviations:
    BVDU
    (E)-5-(2-bromovinyl)-2′-deoxyuridine
    HSV
    herpes simplex virus
    VZV
    varicella zoster virus
    TK
    thymidine kinase
    BVDU-MP
    (E)-5-(2-bromovinyl)-2′-deoxyuridine monophosphate
    BVDU-TP
    (E)-5-(2-bromovinyl)-2′-deoxyuridine triphosphate
    CHO
    Chinese hamster ovary
    TS
    thymidylate synthase
    GCV
    ganciclovir
    ACV
    aciclovir
    AP-1
    activator protein 1
    fmk
    fluoromethyl ketone
    PARP
    poly(ADP-ribose) polymerase
    AIF
    apoptosis inducing factor
    ERK2
    extracellular signal receptor-regulated kinase
    pAb
    polyclonal antibody
    PI
    propidium iodide
    PBS
    phosphate-buffered saline
    FITC
    fluorescein isothiocyanate
    dThd
    deoxythymidine
    DN-FADD
    dominant-negative-Fas-associated death domain
    SCGE
    single cell gel electrophoresis
    BrdU
    5-bromo-2′-deoxyuridine
    CREB/ATF
    cAMP response element-binding protein/activating transcription factor
    MMS
    methyl methansulfonate
    zXXXX-fmk
    N-benzyloxycarbonyl-XXXX-fluoromethyl ketone (where X is an amino acid)
    • Received May 2, 2002.
    • Accepted November 4, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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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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Research ArticleArticle

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

Maja T. Tomicic, Claudia Friedrichs, Markus Christmann, Peter Wutzler, Rudolf Thust and Bernd Kaina
Molecular Pharmacology February 1, 2003, 63 (2) 439-449; DOI: https://doi.org/10.1124/mol.63.2.439

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Research ArticleArticle

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

Maja T. Tomicic, Claudia Friedrichs, Markus Christmann, Peter Wutzler, Rudolf Thust and Bernd Kaina
Molecular Pharmacology February 1, 2003, 63 (2) 439-449; DOI: https://doi.org/10.1124/mol.63.2.439
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