Interferon-alpha enhances CD95L-induced apoptosis of human malignant glioma cells.
CD95 ligand (CD95L)-induced apoptosis is a novel immunotherapeutic approach to malignant glioma. Here, we report that interferon-alpha (IFN-alpha) sensitizes LN-229 and T98G human malignant glioma cells to CD95L-induced apoptosis. In contrast to the effects of IFN-gamma and TNF-alpha which sensitize glioma cells to CD95 antibody-induced apoptosis in part by enhancing CD95 expression, IFN-alpha has no effect on CD95 expression at the cell surface of LN-229 and T98G cells. To confirm that changes in CD95 expression are not required for the effects of IFN-alpha, we show that IFN-alpha enhances CD95L-induced apoptosis even in CD95-transfected LN-308 glioma cells. These LN-308 cells have little endogenous CD95 expression but express high levels of CD95 from a stably integrated CD95 expression plasmid. The sensitizing effects of IFN-alpha appear to be independent of cell cycle effects of IFN-alpha and are unaffected by ectopic expression of the bcl-2 proto-oncogene. IFN-alpha enhances CD95L-induced activation of caspase-3, a critical mediator of CD95L-induced cell death. IFN-alpha also increases the cytotoxic effects of BCNU, teniposide and cytarabine in both cell lines, and of vincristine in LN-229 cells. Doxorubicin and 5-fluorouracil toxicity are unaffected by IFN-alpha. IFN-alpha may be a useful adjunct to novel strategies of immunochemotherapy for malignant gliomas that target CD95-mediated apoptosis.
Department of Neurology, University of Tübingen, School of Medicine, Germany.
W
W
Roth
B
B
Wagenknecht
J
J
Dichgans
M
M
Weller
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002330:Carmustine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases; D002462:Cell Membrane / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression / Q000502:physiology; D019254:Genes, bcl-2 / Q000235:genetics; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism / Q000494:pharmacology*
D018906:Antineoplastic Agents, Alkylating; D016898:Interferon-alpha; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D002330:Carmustine