Apoptotic death by ceramide: will the real killer please stand up?

Many studies have shown that the addition of ceramide to an incubation medium, or procedures that lead to increased ceramide concentrations, can begin a process that leads to slowing of cell growth or apoptotic cell death. Only a few studies have examined the nature of the accumulating ceramide: is it composed of a fatty acid and sphinganine, or a fatty acid and sphingosine? Of the studies involving addition of ceramide to a cell culture, almost all have found that the sphingosine amide is active, not the sphinganine amide. Nearly all of these studies have utilized the rare form of ceramide, containing an acetyl group rather than the commonly found palmitoyl, stearoyl, or longer group. Acetyl sphingosine produces some unexpected effects with cells, the most striking being the formation of reactive oxygen species and mitochondrial damage. This mitochondrial damage appears to be an essential step in apoptosis. The possibility should be considered that the reactive oxygen species appear as the result of oxidation of the allylic alcohol group in unsaturated ceramides. This question is very relevant to a host of ceramide functions, particularly cancer chemotherapy and cell growth.