Abstract
Several studies have suggested that diacylglycerol can affect the induction of apoptosis induced by toxicants and ceramide. The present study demonstrates that clinically relevant concentrations of the chemotherapeutic drugs daunorubicin and mitoxantrone (0.2–1 μM) transiently stimulated concurrently with sphingomyelin-derived ceramide generation and diacylglycerol and phosphorylcholine production within 4 to 10 min via phospholipase C hydrolysis of phosphatidylcholine. Pretreatment of cells with the xanthogenate compound D609, a potent inhibitor of phosphatidylcholine-phospholipase C, led to significant inhibition of drug triggered diacylglycerol and phosphorylcholine production and to a sustained increase in ceramide levels for a period up to 2 h. Moreover, D609 pretreatment induced both cell death and ceramide generation at daunorubicin and mitoxantrone concentrations previously shown to be ineffective (i.e., 0.1 μM). These results underline the importance of diacylglycerol in the regulation of programmed cell death and strongly argue for a balance between apoptotic (ceramide) and survival (diacylglycerol) signal transducers.
Footnotes
- Received July 27, 1998.
- Accepted September 25, 1998.
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Send reprint requests to: Dr. Ali Bettaı̈eb, CJF Institut National de la Santé et de la Recherche Medicale 95–03, Institut Claudius Régaud, 20 rue du Pont St. Pierre, 31052 Toulouse, France. E-mail:inserm{at}icr.fnclcc.fr
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This work was supported by grants from the Actions Concertées Coordonnées-Sciences du Vivant ACCSV8:9508008 (to G.L.), La Fédération Nationale des Centres de Lutte Contre le Cancer (to J.P.J. and T.L.), the Conseil Régional Midi-Pyrénées (to J.P.J. and T.L.), l’Association pour la Recherche sur le Cancer Grants 6749 (to G.L.), 3002 (to T.L.), and 2069 (to J.P.J.), and by La Ligue Nationale Contre le Cancer (to G.L.), and la Société Française d’Hématologie, Paris (to A.B.).
- The American Society for Pharmacology and Experimental Therapeutics
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