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Vol. 55, Issue 1, 118-125, January 1999

Daunorubicin- and Mitoxantrone-Triggered Phosphatidylcholine Hydrolysis: Implication in Drug-Induced Ceramide Generation and Apoptosis

Ali Bettaïeb, Isabelle Plo, Véronique Mansat-De Mas, Anne Quillet-Mary, Thierry Levade, Guy Laurent, and Jean-Pierre Jaffrézou

Contrat Jeune Formation Institut National de la Santé et de la Recherche Medicale 95-03, Institut Claudius Régaud (A.B., I.P., V.M., A.Q., G.L., J.P.J.), Institut National de la Santé et de la Recherche Medicale U466, Centre Hospitalier Universitaire Rangueil (T.L.), and the Service d'Hématologie, Centre Hospitalier Universitaire Purpan (G.L.), Toulouse, France

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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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