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Tumor Biology

The CD95 (APO-1/Fas) System Mediates Drug-induced Apoptosis in Neuroblastoma Cells

Simone Fulda, Hauke Sieverts, Claudia Friesen, Ingrid Herr and Klaus-Michael Debatin
Simone Fulda
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Hauke Sieverts
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Claudia Friesen
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Ingrid Herr
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Klaus-Michael Debatin
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DOI:  Published September 1997
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Abstract

Anticancer agents have been shown to trigger apoptosis in chemosensitive tumors such as neuroblastomas. We previously identified activation of the CD95 system as one of the key mechanisms for doxorubicin-induced apoptosis in leukemic T cells. Here, we report that therapeutic concentrations of doxorubicin, cisplatinum, and VP-16 led to induction of CD95 receptor and CD95 ligand (CD95-L) that mediated cell death in chemosensitive neuroblastoma cells. Using F(ab′)2 anti-CD95 antibody fragments to interfere with CD95-L-receptor interaction markedly reduced apoptosis induced by those drugs in vitro. Cyclosporin A inhibited induction of CD95 mRNA and CD95-L mRNA and blocked drug-mediated apoptosis. Drug-induced apoptosis involved activation of caspases (interleukin 1β-converting enzyme/Ced-3-like proteases) and processing of the prototype caspase substrate PARP and was completely blocked by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a peptide inhibitor of caspases. In addition, neuroblastoma cells that were resistant to CD95-triggered apoptosis also displayed cross-resistance to chemotherapeutic agents. These data provide new clues for understanding the molecular requirements for drug-induced apoptosis in chemosensitive neuroblastoma cells by demonstrating that cell death was mediated via the CD95-L-receptor system and may open new avenues for targeting drugresistance of neuroblastoma.

Footnotes

  • ↵1 This work was supported by grants from the Deutsche Forschungsgemeinschaft (to K-M. D.), the Tumor Center Heidelberg/Mannheim, and the Deutsche Leukämieforschungshilfe.

  • Received March 24, 1997.
  • Accepted July 3, 1997.
  • ©1997 American Association for Cancer Research.
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September 1997
Volume 57, Issue 17
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The CD95 (APO-1/Fas) System Mediates Drug-induced Apoptosis in Neuroblastoma Cells
Simone Fulda, Hauke Sieverts, Claudia Friesen, Ingrid Herr and Klaus-Michael Debatin
Cancer Res September 1 1997 (57) (17) 3823-3829;

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The CD95 (APO-1/Fas) System Mediates Drug-induced Apoptosis in Neuroblastoma Cells
Simone Fulda, Hauke Sieverts, Claudia Friesen, Ingrid Herr and Klaus-Michael Debatin
Cancer Res September 1 1997 (57) (17) 3823-3829;
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