The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells.
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.
Fulda
S
S
Division of Hematology/Oncology, University Children's Hospital, German Cancer Research Center, Heidelberg.
Sieverts
H
H
Friesen
C
C
Herr
I
I
Debatin
K M
KM
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
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