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Título

New oleyl glycoside as anti-cancer agent that targets on neutral sphingomyelinase

AutorRomero-Ramírez, Lorenzo CSIC ORCID; García-Álvarez, Isabel; Casas, Josefina CSIC ORCID ; Barreda-Manso, M. Asunción CSIC ORCID; Yanguas-Casás, Natalia; Nieto-Sampedro, Manuel CSIC; Fernández-Mayoralas, Alfonso CSIC ORCID
Palabras claveSphingomyelin
ER stress
Ceramide
Glycosphingolipids
Apoptosis
Fecha de publicación2015
EditorElsevier
CitaciónBiochemical Pharmacology 97: 158-172 (2015)
ResumenWe 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.
Versión del editorhttp://dx.doi.org/10.1016/j.bcp.2015.07.009
URIhttp://hdl.handle.net/10261/126865
DOI10.1016/j.bcp.2015.07.009
Identificadoresdoi: 10.1016/j.bcp.2015.07.009
issn: 0006-2952
e-issn: 1873-2968
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