期刊
CANCER LETTERS
卷 181, 期 1, 页码 55-64出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/S0304-3835(02)00049-6
关键词
cancer; ceramide; apoptosis; chemotherapy
类别
资金
- NIMH NIH HHS [MH61934-03] Funding Source: Medline
- NINDS NIH HHS [NS11853] Funding Source: Medline
A variety of anti-cancer drugs elevate endogenous ceramide, thereby inducing apoptosis in tumor cells. Recently, we have introduced novel ceramide analogs of the P-hydroxy alkyl amide type, which trigger pro-apoptotic signaling pathways without prior elevation of endogenous ceramide. They induce apoptosis specifically in rapidly dividing neuroblastoma cells, but not in resting or differentiated cells. We characterize new ceramide mimics that have been derived from N-acylation of serinol (S), diethanolamine (13), propanolamine (P), and tris(hydroxy-methyl)methylamine (T) with myristic (14), palmitic (16). or oleic (18) acid. The water solubility of these compounds exceeds that of ceramide by more than 100-fold (up to 5 mM). Apoptosis of human neuroblastoma, glioma, medulloblastoma, and adenocarcinoma cells is induced by N-(2-hydroxy-1-(hydroxymethyl)ethyl)-palmitoylamide, C16-serinol (S16), N-(2-hydroxy-1-(hydroxymethyl)ethyl)-oleoylamide, C18-serinol (S 18), N-bis(2-hydroxyethyl)-myristoyl-amide (13 16), and N-tris(hydroxymethyl)methyl-oleoylamide (T18) within 60 min of incubation, and is completed even after removal of the compound from the medium. This is most likely due to a rapid uptake of the analogs followed by their slow release from the cells. Alteration of the acyl chain length to less than 14 methylene units, removal of the amino group, or reducing the number of hydroxyalkyl residues to less than two significantly lowers or eliminates the proapoptotic potential of these compounds. The target specificity of novel ceramide analogs for tumor cells, their water solubility, and fast pro-apoptotic mechanism indicates a high therapeutic potential for cancer treatment. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据