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[Cancer Research 57, 3823-3829, September 1, 1997]
© 1997 American Association for Cancer Research
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The CD95 (APO-1/Fas) System Mediates Drug-induced Apoptosis in Neuroblastoma Cells1

Simone Fulda, Hauke Sieverts, Claudia Friesen, Ingrid Herr and Klaus-Michael Debatin2

Division of Hematology/Oncology, University Children's Hospital, and Division of Molecular Oncology, German Cancer Research Center, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany

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 1ß-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.

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

2 Current address and to whom requests for reprints should be addressed, at University Children's Hospital, Prittwitzstrasse 43, D-89075 Ulm, Germany. Phone: 49-731 502 7700; Fax: 49-731 502 6681.

Received 3/24/97. Accepted 7/ 3/97.




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A Matter of Life and Cell Death
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Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells
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Blood, June 15, 1998; 91(12): 4624 - 4631.
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