title: Implication of radical oxygen species in ceramide generation, c-Jun N-terminal kinase activation and apoptosis induced by daunorubicin.
abstract: Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their cytotoxic effect. We observed that early ceramide generation (within 6-10 min) through neutral sphingomyelinase stimulation was inhibitable by the antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after 6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale E9910, Institut Claudius Régaud, Toulouse, France.
authors.forename: V
authors.initials: V
authors.lastname: Mansat-de Mas
authors.forename: C
authors.initials: C
authors.lastname: Bezombes
authors.forename: A
authors.initials: A
authors.lastname: Quillet-Mary
authors.forename: A
authors.initials: A
authors.lastname: Bettaïeb
authors.forename: A D
authors.initials: AD
authors.lastname: D'orgeix
authors.forename: G
authors.initials: G
authors.lastname: Laurent
authors.forename: J P
authors.initials: JP
authors.lastname: Jaffrézou
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002518:Ceramides / Q000096:biosynthesis*; D003630:Daunorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002518:Ceramides; D016166:Free Radical Scavengers; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; C020972:pyrrolidine dithiocarbamic acid; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D000111:Acetylcysteine; D003630:Daunorubicin