Since its identification, nSMase2 has emerged as a major candidate for stress-induced ceramide production and a number of anti-cancer drugs have been shown to exert effects on nSMase2. In MCF-7 cells, daunorubicin upregulated cellular N-SMase activity and ceramide levels (Ito et al., 2009). Notably, daunorubicin specifically upregulated both nSMase2 mRNA and protein levels but had no effects on nSMase1 and nSMase3. Further analysis revealed that nSMase2 was important in mediating daunorubicin-induced cell death and that several Sp1 motifs in the nSMase2 promoter region were important for transcriptional induction by daunorubicin (Ito et al., 2009). Additionally, nSMase2 overexpression enhanced cell death induced by either staurosporine or C(2)-ceramide in oligodendrocytes (Goswami et al., 2005). In aortic smooth muscle cells, apolipoprotein C-I induced N-SMase activity, ceramide levels, and apoptosis which was abolished by treatment with the nSMase2 inhibitor, GW4869 (Kolmakova et al., 2004).
