MECHANISMS OF CYTOTOXICITY OF MAJOR ANTIT UMOR AGENTS AND THE SPHINGOMYELIN-CERAMIDE SIGNALING PATHWAY

Recent studies demonstrate that cytokines, differentiating drugs, and antitumor agents trigger an intracellular signalling pathway character ized by sphingomyelinase activation, plasma membrane-associated sphing omyelin hydrolysis and subsequent ceramide generation (sphingomyelin-c eramide pathway). Ceramide, in turn, may induce various biological eff ects including proliferation, apoptosis, and differentiation, dependin g on the agonist and the cellular model. These findings may have impor tant implications in cancer therapy since this signalling pathway is i nvolved in the cytotoxicity mechanism of major antitumor agents such a s ionizing radiations, anthracyclines, and aracytine (and likely many others). Furthermore, this signalling cascade appears to be efficientl y regulated by several parameters at two distinct levels: (I) upstream of ceramide generation, by the content of hydrolysable sphingomyelin pool and the magnitude of sphingomyelinase activation; (2) downstream of ceramide generation, by protein kinase activities, diacylglycerol c ontent, oncogenes products such as c-Jun and Bcl-2, and functional cap acities of transcriptional factors such as NF-kappa B and AP-1. Theref ore, it is conceivable that, in some tumor cells, this signalling casc ade may be altered at different(s) level(s) in relation with metabolic or genotypic modifications, leading to drug and/or radiation resistan ce. Better knowledge of the molecular basis of drug/radiation-activate d sphingomyelin-ceramide signalling pathway may offer promising perspe ctives for pharmacological manipulations to improve the cytotoxicity o f anti-tumor agents.