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

EMBO J. 1996 May 15;15(10):2417-24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Apoptosis / drug effects*
  • Ceramidases
  • Ceramides / biosynthesis*
  • Daunorubicin / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Fumonisins*
  • HL-60 Cells / drug effects
  • HL-60 Cells / metabolism
  • Humans
  • Hydrolysis
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mycotoxins / pharmacology
  • Signal Transduction / drug effects
  • Sphingomyelins / metabolism*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • Ceramides
  • Enzyme Inhibitors
  • Fumonisins
  • Mycotoxins
  • Sphingomyelins
  • fumonisin B1
  • Amidohydrolases
  • Ceramidases
  • Daunorubicin