TY - JOUR T1 - Daunorubicin- and Mitoxantrone-Triggered Phosphatidylcholine Hydrolysis: Implication in Drug-Induced Ceramide Generation and Apoptosis JF - Molecular Pharmacology JO - Mol Pharmacol SP - 118 LP - 125 DO - 10.1124/mol.55.1.118 VL - 55 IS - 1 AU - Ali Bettaïeb AU - Isabelle Plo AU - Véronique Mansat-De Mas AU - Anne Quillet-Mary AU - Thierry Levade AU - Guy Laurent AU - Jean-Pierre Jaffrézou Y1 - 1999/01/01 UR - http://molpharm.aspetjournals.org/content/55/1/118.abstract N2 - 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. ER -