Ceramide mediates radiation-induced death of endothelium

The sphingomyelin (SM) pathway is an ubiquitous, evolutionarily conserved s ignaling system, analogous to conventional systems such as the cAMP and pho sphoinositide pathways. Ceramide is generated from SM by the action of a ne utral or acid SMase, or by de novo synthesis coordinated through the enzyme ceramide synthase. Once generated, ceramide may serve as a second messenge r in signaling responses to physiologic or environmental stimuli, or may be converted to a variety of structural or effector molecules. In the radiati on response, ceramide serves as a second messenger in initiating apoptosis, while some of its metabolites block apoptosis. In certain cells, such as e ndothelial, lymphoid and haematopoietic cells, ceramide mediates apoptosis while in others ceramide may serve only as a co-signal for or play no role in the death response. Regulated ceramide metabolism may determine the bala nce between pro- and anti-apoptotic signals, and hence, the intensity of th e apoptotic response, thus constituting a mechanism of radiation sensitivit y or resistance. This paradigm may offer new opportunities for modulation o f the radiation effects in the treatment of cancer. Chemical modifiers of c eramide metabolism may be useful to enhance the therapeutic effects or redu ce the toxicity of radiation treatment.