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

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• 作者：Lorenzo Romero-Ramí ; rez^a ; ^{lromeroramirez@sescam.jccm.es" class="auth_mail" title="E-mail the corresponding author} ; Isabel Garcí ; a-Á ; lvarez^a ; ^b ; Josefina Casas^c ; M.Asunció ; n Barreda-Manso^a ; ^d ; Natalia Yanguas-Casá ; s^d ; Manuel Nieto-Sampedro^a ; ^d ; Alfonso Ferná ; ndez-Mayoralas^b ; ^{alfonso.mayoralas@csic.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：UPLC-MS ; ultra performance liquid chromatography-mass spectrometry ; NMR ; nuclear magnetic resonance ; MTT ; methylthiazol tetrazolium ; IC50 ; 50% inhibitory dose ; UPRE ; unfolding protein response element ; ERSE ; endoplasmic reticulum stress element ; Cer ; ceramide ; SMs ; phingomyelin ; GlcCer ; glucosylceramide ; GCS ; glucosylceramide synthase ; SMS ; sphingomyelin synthase ; XBP-1 ; X-box binding protein 1
• 刊名：Biochemical Pharmacology
• 出版年：2015
• 出版时间：15 September 2015
• 年：2015
• 卷：97
• 期：2
• 页码：158-172
• 全文大小：2258 K

文摘

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 伪-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 伪-anomer caused a drastic accumulation of ceramide and glucosylceramide and reduction of lactosylceramide and GM3 ganglioside at concentrations above a threshold of 20 渭M. In order to understand how ceramide levels increase in response to 伪-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 伪-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.