Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes

We examined the biological effects of the ceramide analogues (1S,2R)-2-N-myristoylamino-1-phenyl-1-propanol (D-e-MAPP) and (1R,2R)-2-N-myristoylamino-1-(4-nitrophenyl)-1,3-propandiol (D-NMAPPD) on human HaCaT keratinocytes and human melanoma cells. We could demonstrate that D-e-MAPP and D-NMAPPD are able to suppress acid ceramidase activity. The elevation of the endogenous level of ceramide is followed by induction of apoptosis and suppression of proliferation in HaCaT keratinocytes. Moreover, we recently identified a group of human melanoma cell populations which are heterogeneously susceptible to C₂-ceramide-mediated apoptosis. Studies with these melanoma cells revealed correlation between ceramide-mediated apoptosis and D-NMAPPD-induced apoptosis, confirming the effect of this inhibitor on ceramide signaling in human melanoma cells. These findings suggest ceramidase inhibitors as a potential new therapeutical class of antiproliferative and cytostatic drugs.