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.
Footnotes
- Received July 8, 1999.
- Accepted August 6, 1999.
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Send reprint requests to: Dr. Jean-Pierre Jaffrézou, Institut National de la Sante et de la Recherche Medicale E9910, Institut Claudius Régaud, 20 rue du Pont Saint-Pierre, Toulouse Cedex, 31052 France. E-mail: jaffrezou{at}icr.fnclcc.fr
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1 This work was supported by grants from La Fédération Nationale des Centres de Lutte Contre le Cancer (J-P.J., G.L.), L’Association pour la Recherche contre le Cancer 9296 (G.L.), 9788 (J-P.J.), and by La Ligue Nationale Contre le Cancer (J-P.J.). V.M.D. is an Institut National de la Sante et de la Recherche Medicale fellow and C.B. is a recipient of a study grant from la Ligue Nationale contre le Cancer.
- The American Society for Pharmacology and Experimental Therapeutics
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