Department of Medical Chemistry, Biochemistry and Biotechnology, Center of Excellence on Neurodegenerative Diseases, University of Milano, 20090 Segrate, Italy.
J Lipid Res. 2010 Jul;51(7):1832-40. doi: 10.1194/jlr.M004010. Epub 2010 Mar 1.
The dihydroceramide, ceramide, sphingomyelin, lactosylceramide, and ganglioside species of A2780 human ovarian carcinoma cells treated with the synthetic retinoids N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) in culture were characterized by ESI-MS. We characterized 32 species of ceramide and dihydroceramide, 15 of sphingomyelin, 12 of lactosylceramide, 9 of ganglioside GM2, and 6 of ganglioside GM3 differing for the long-chain base and fatty acid structures. Our results indicated that treatment with both 4-HPR and 4-oxo-4-HPR led to a marked increase in dihydroceramide species, while only 4-oxo-4-HPR led to a minor increase of ceramide species. Dihydroceramides generated in A2780 cells in response to 4-HPR or 4-oxo-4-HPR differed for their fatty acid content, suggesting that the two drugs differentially affect the early steps of sphingolipid synthesis. Dihydroceramides produced upon treatments with the drugs were further used for the synthesis of complex dihydrosphingolipids, whose levels dramatically increased in drug-treated cells.
用 ESI-MS 对用合成视黄醇 N-(4-羟基苯基)视黄酰胺（fenretinide，4-HPR）和 4-氧代-N-(4-羟基苯基)视黄酰胺（4-oxo-4-HPR）处理的 A2780 人卵巢癌细胞中的二氢神经酰胺、神经酰胺、神经鞘磷脂、乳糖神经酰胺和神经节苷脂进行了表征。我们鉴定了 32 种神经酰胺和二氢神经酰胺、15 种神经鞘磷脂、12 种乳糖神经酰胺、9 种神经节苷脂 GM2 和 6 种神经节苷脂 GM3，它们在长链碱基和脂肪酸结构上有所不同。结果表明，4-HPR 和 4-oxo-4-HPR 的处理均导致二氢神经酰胺种类明显增加，而只有 4-oxo-4-HPR 导致神经酰胺种类略有增加。A2780 细胞中响应 4-HPR 或 4-oxo-4-HPR 产生的二氢神经酰胺在脂肪酸含量上存在差异，这表明这两种药物对鞘脂合成的早期步骤有不同的影响。用这些药物处理后产生的二氢神经酰胺进一步用于合成复杂的二氢神经鞘脂，其在药物处理的细胞中水平显著增加。
