title: The topoisomerase inhibitors camptothecin and etoposide induce a CD95-independent apoptosis of activated peripheral lymphocytes.
abstract: The effect of etoposide and camptothecin, two topoisomerase inhibitors directed against topoisomerases II and I, respectively, was evaluated on human peripheral blood lymphocytes. Etoposide and camptothecin induced apoptosis of mitogen-activated but not resting CD4+ and CD8+ T lymphocytes. Cell sensitivity to these agents required G1 to S-phase transition of the cell cycle. Conversely, daunorubicin, an intercalating agent and topoisomerase II inhibitor, induced apoptosis of both resting and activated lymphocytes. Although etoposide and camptothecin induced CD95-ligand mRNA expression, drug-induced apoptosis of activated human lymphocytes was not inhibited by CD95 antagonists. Drug-induced cell death was also not inhibited by p55 TNFR-Ig fusion protein. Activation of the caspases cascade was suggested by the partial inhibitory effect of the tripeptide zVAD-fmk and documented by activation of caspase 3. Finally etoposide and camptothecin induced a rapid production of ceramide in activated but not resting peripheral blood lymphocytes, suggesting that ceramide might initiate the signaling apoptotic cascade in sensitive cells.
authors.affiliation: Laboratory of Immunology, INSERM U503 UCBL, Hôpital E. Herriot, 69437 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Ferraro
authors.forename: L
authors.initials: L
authors.lastname: Quemeneur
authors.forename: S
authors.initials: S
authors.lastname: Fournel
authors.forename: A F
authors.initials: AF
authors.lastname: Prigent
authors.forename: J P
authors.initials: JP
authors.lastname: Revillard
authors.forename: N
authors.initials: N
authors.lastname: Bonnefoy-Berard
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000473:pathology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D019014:fas Receptor
chemical_list: D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D059004:Topoisomerase I Inhibitors; D019014:fas Receptor; D005047:Etoposide; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin