Implication of Radical Oxygen Species in Ceramide Generation, c-Jun N-Terminal Kinase Activation and Apoptosis Induced by Daunorubicin

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- acetylcyste...

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Bibliographic Details
Published in:Molecular pharmacology 1999-11, Vol.56 (5), p.867-874
Main Authors: Mas, Véronique Mansat-De, Bezombes, Christine, Quillet-Mary, Anne, Bettaieb, Ali, D’orgeix, Aurélie de Thonel, Laurent, Guy, Jaffrézou, Jean-Pierre
Format: Article
Language:English
Subjects:
Acetylcysteine - pharmacology
Antineoplastic Agents - pharmacology
Antioxidants - pharmacology
Apoptosis
Cellular Biology
Ceramides - biosynthesis
Daunorubicin - pharmacology
Drug Interactions
Electron Transport - drug effects
Enzyme Activation
Free Radical Scavengers - antagonists & inhibitors
Free Radical Scavengers - pharmacology
Hematology
Human health and pathology
Humans
Hydrogen Peroxide - metabolism
JNK Mitogen-Activated Protein Kinases
Life Sciences
Mitochondria - drug effects
Mitochondria - metabolism
Mitogen-Activated Protein Kinases - metabolism
Pyrrolidines - pharmacology
Reactive Oxygen Species - metabolism
Sphingomyelin Phosphodiesterase - metabolism
Thiocarbamates - pharmacology
Transcription Factor AP-1 - metabolism
U937 Cells
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.56.5.867