RT Journal Article
SR Electronic
T1 The CD95 (APO-1/Fas) System Mediates Drug-induced Apoptosis in Neuroblastoma Cells
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 3823
OP 3829
VO 57
IS 17
A1 Fulda, Simone
A1 Sieverts, Hauke
A1 Friesen, Claudia
A1 Herr, Ingrid
A1 Debatin, Klaus-Michael
YR 1997
UL http://cancerres.aacrjournals.org/content/57/17/3823.abstract
AB 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. ©1997 American Association for Cancer Research.