title: The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells.
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 1beta-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 drug resistance of neuroblastoma.
authors.affiliation: Division of Hematology/Oncology, University Children's Hospital, German Cancer Research Center, Heidelberg.
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.forename: H
authors.initials: H
authors.lastname: Sieverts
authors.forename: C
authors.initials: C
authors.lastname: Friesen
authors.forename: I
authors.initials: I
authors.lastname: Herr
authors.forename: K M
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation; D019014:fas Receptor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007128:Immunoglobulin Fragments; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D005047:Etoposide; D004317:Doxorubicin; D016572:Cyclosporine; D003546:Cysteine Endopeptidases; D002945:Cisplatin