Sphingolipid metabolism, apoptosis and resistance to cytotoxic agents: can we interfere?

Sphingolipid metabolism assumes a key role in the complex mechanisms regulating cellular stress responses to environmental stressors, including cytotoxic agents. The sphingolipid metabolic pathways, therefore, are promising sources of anticancer therapeutic strategies. Several sphingolipid metabolites have recently been shown to have bioactivity, and their individual contributions to the regulatory pathways that govern cell growth are currently being established in mammalian cells and yeast. The Sphingomyelin (SM) cycle represents a novel antiproliferative, sphingolipid-mediated signal transduction pathway that regulates cell cycle arrest, differentiation, and apoptosis in response to growth factor deprivation, cytokines, ionizing radiation, heat, and chemotherapy. Ceramide, the putative second messenger of the SM cycle, has been proposed as a molecular sensor of injury and assumes a fundamental role in the cellular stress response. This review will discuss sphingolipid metabolism within the context of the cellular stress response, the contribution of sphingolipids to chemotherapy-mediated apoptosis, and suggest novel sphingolipid-based strategies in the treatment of malignant disease.