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. 1996 May 15;15(10):2417–2424.

Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis.

J P Jaffrézou 1, T Levade 1, A Bettaïeb 1, N Andrieu 1, C Bezombes 1, N Maestre 1, S Vermeersch 1, A Rousse 1, G Laurent 1
PMCID: PMC450173  PMID: 8665849

Abstract

The nature of the signaling pathway(s) which initiate drug-triggered apoptosis remains largely unknown and is of fundamental importance in understanding cell death induced by chemotherapeutic agents. Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis, stimulated two distinct cycles of sphingomyelin hydrolysis (approximately 20% decrease at 1 microM) within 4-10 min and 60-75 min with concomitant ceramide generation. We demonstrate that the increase in ceramide levels, which precedes apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide synthase. Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation or apoptosis. In conclusion, we provide evidence that daunorubicin-triggered apoptosis is mediated by a signaling pathway which is initiated by an early sphingomyelin-derived ceramide production.

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