Sphingolipid Modulation: A Strategy for Cancer Therapy

Antonio      Delgado; Gemma      Fabrias; Carmen      Bedia; Josefina      Casas; Jose Luis      Abad

Abstract

Sphingolipids are membrane lipids that play important roles in the regulation of cell functions and homeostasis. Alterations in their metabolism have been associated with several pathologies. For this reason, therapeutic strategies based on the design of small molecules to restore sphingolipid levels to their physiological condition have rapidly emerged. In addition, some of these new chemical entities, even if they fail to succeed along the pipeline, can become valuable pharmacological tools for the study of sphingolipid function. Implications of altered sphingolipid metabolism in cancer progression have allowed the identification of new targets for the development of potential anticancer agents. Based on these premises, this review is focused on the most recent achievements in the field, with special attention to the development of small molecules, mainly enzyme inhibitors, able to disrupt some of the key sphingolipid metabolic pathways implicated in cancer progression. On the other hand, metabolic dysregulation can also be modulated by the use of sphingolipid analogs, which can alter the sphingolipid balance driving cells to death or survival and thus becoming useful candidates for subsequent drug development.

Keywords: Sphingolipids, Enzyme inhibitors, Analogs, Modulation, Metabolism, dhCer, cyclopropane, Cer-recognizing factors, denocarcinoma