fumonisin-b1 and Lymphoma--Large-B-Cell--Diffuse

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.

Topics: Amidohydrolases; Apoptosis; Ceramidases; Ceramides; Daunorubicin; Enzyme Inhibitors; Fumonisins; HL-60 Cells; Humans; Hydrolysis; Lymphoma, Large B-Cell, Diffuse; Mycotoxins; Signal Transduction; Sphingomyelins; Tumor Cells, Cultured