Pharmacological modulation of sphingolipids and role in disease and cancer cell biology.

Sphingolipids comprise a family of bioactive lipids that exert antagonizing roles in diverse cellular functions such as cell proliferation, growth arrest or apoptosis. Synthesized in the ER/Golgi, sphingolipids are subsequently distributed to different compartments, most predominantly in the plasma membrane, where they integrate signaling platforms. In addition to its precursor role in the synthesis of complex glycosphingolipids, ceramide has been identified as a cell death effector and its generation increases in response to apoptotic stimuli including stress, radiation, chemotherapy, and death ligands. In contrast, sphingosine-1-phosphate (S1P) has been mainly characterized as an antiapoptotic sphingolipid mediating cell proliferation and survival. Thus, the relative balance between ceramide and SIP has important implications in disease pathogenesis, and therefore the pharmacological modulation of enzymes involved in regulation of the ceramide to SIP ratio could constitute a novel therapeutic approach for the treatment of human diseases and cancer.