title: New oleyl glycoside as anti-cancer agent that targets on neutral sphingomyelinase.
abstract: We designed and synthesized two anomeric oleyl glucosaminides as anti-cancer agents where the presence of a trifluoroacetyl group close to the anomeric center makes them resistant to hydrolysis by hexosaminidases. The oleyl glycosides share key structural features with synthetic and natural oleyl derivatives that have been reported to exhibit anti-cancer properties. While both glycosides showed antiproliferative activity on cancer cell lines, only the α-anomer caused endoplasmic reticulum (ER) stress and cell death on C6 glioma cells. Analysis of sphingolipids and glycosphingolipds in cells treated with the glycosides showed that the α-anomer caused a drastic accumulation of ceramide and glucosylceramide and reduction of lactosylceramide and GM3 ganglioside at concentrations above a threshold of 20 μM. In order to understand how ceramide levels increase in response to α-glycoside treatment, further investigations were done using specific inhibitors of sphingolipid metabolic pathways. The pretreatment with 3-O-methylsphingomyelin (a neutral sphingomyelinase inhibitor) restored sphingomyelin levels together with the lactosylceramide and GM3 ganglioside levels and prevented the ER stress and cell death caused by the α-glycoside. The results indicated that the activation of neutral sphingomyelinase is the main cause of the alterations in sphingolipids that eventually lead to cell death. The new oleyl glycoside targets a key enzyme in sphingolipid metabolism with potential applications in cancer therapy.
authors.affiliation: Hospital Nacional de Parapléjicos, SESCAM, Finca la Peraleda s/n, 45071 Toledo, Spain. Electronic address: lromeroramirez@sescam.jccm.es.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Romero-Ramírez
authors.affiliation: Hospital Nacional de Parapléjicos, SESCAM, Finca la Peraleda s/n, 45071 Toledo, Spain; Instituto de Química Orgánica General, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: García-Álvarez
authors.affiliation: RUBAM Institut de Química Avançada de Catalunya, CSIC, Jordi Girona, 18, 08034 Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: Hospital Nacional de Parapléjicos, SESCAM, Finca la Peraleda s/n, 45071 Toledo, Spain; Instituto Cajal, CSIC, Avda. Doctor Arce 37, 28002 Madrid, Spain.
authors.forename: M Asunción
authors.initials: MA
authors.lastname: Barreda-Manso
authors.affiliation: Instituto Cajal, CSIC, Avda. Doctor Arce 37, 28002 Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yanguas-Casás
authors.affiliation: Hospital Nacional de Parapléjicos, SESCAM, Finca la Peraleda s/n, 45071 Toledo, Spain; Instituto Cajal, CSIC, Avda. Doctor Arce 37, 28002 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.affiliation: Instituto de Química Orgánica General, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain. Electronic address: alfonso.mayoralas@csic.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Fernández-Mayoralas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006027:Glycosides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D006027:Glycosides; D013108:Sphingomyelin Phosphodiesterase
keywords: Apoptosis; Ceramide; ER stress; Glycosphingolipids; Sphingomyelin