title: Alteration of ceramide 1-O-functionalization as a promising approach for cancer therapy.
abstract: Sphingolipids, which are complex lipidic components of the cell membranes, lie in a key position to modulate the pathways of trans-membrane signaling and allow the cell to adapt to environmental stresses. In malignancies, reduced production of some sphingolipid species able to induce apoptosis such as ceramide and conversely, increased levels of some other metabolites involved in tumor progression and drug resistance of cancer cells, are often described. In this context, the discovery of new chemical entities able to specifically modify ceramide metabolism should offer novel pharmacological tools in cancer therapy. The review dedicates particular attention to the enzymes that modify ceramide at the C1-OH position generating other biologically important sphingolipids in cancer, such as sphingomyelin, ceramide-1-phosphate or glucosylceramide. Findings reported in the literature leading to the development of new chemical entities specifically designed to achieve the above goals have been collected and are discussed. The effects of enzyme inhibitors of sphingomyelin synthase, ceramide kinase and glucosylceramide synthase on cancer cell proliferation, sensitivity to chemotherapeutics, induction of apoptosis or growth of xenografts are presented.
authors.affiliation: Université Paul Sabatier, Toulouse Cedex, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ballereau
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Yves
authors.initials: Y
authors.lastname: Genisson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Andrieu-Abadie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; C065576:ceramide 1-phosphate; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase