Modification of ceramide metabolism increases cancer cell sensitivity to cytotoxics.
Modification of ceramide metabolism increases cancer cell sensitivity to cytotoxics.
复制标题
DOI：
10.3892/ijo.15.3.541
复制
发表时间：
1999-09
影响因子：
5.2
通讯作者：
Anthony Lucci;T. Han;Yong-Yu Liu;Armando E. Giuliano;M. Cabot
中科院分区：
文献类型：
--
作者：
Anthony Lucci;T. Han;Yong-Yu Liu;Armando E. Giuliano;M. Cabot
在先前的报告中，我们证明了MCF-7-AdrR细胞（阿霉素抗性）对神经酰胺不敏感，而MCF-7野生型细胞敏感。还显示耐药细胞具有增加的将神经酰胺转化为葡糖神经酰胺的能力。在这里，我们证明，阻断神经酰胺转化为葡糖神经酰胺增加MCF-7-AdrR细胞的神经酰胺以及抗肿瘤药物的敏感性。用阿霉素处理MCF-7细胞引起神经酰胺增加5倍，并引起寡核小体碎裂，这是细胞凋亡的特征。在相似的处理条件下，MCF-7-AdrR细胞中不产生神经酰胺。在MCF-7-AdrR细胞中，C6-神经酰胺和他莫昔芬都没有细胞毒性;然而，在C6-神经酰胺治疗方案中加入他莫昔芬将细胞活力降低至42%并引起细胞凋亡。只有在他莫昔芬存在的情况下，用阿霉素处理MCF-7-AdrR细胞才能促进神经酰胺的增加，在这种情况下，神经酰胺增加7倍，细胞活力降低至50%。使用另一种阻断神经酰胺糖基化的药物RU 486（米非司酮）以剂量依赖性方式增加MCF-7-AdrR细胞对阿霉素的敏感性。我们的数据表明，阻断神经酰胺糖基化的药物增强了细胞对神经酰胺和化疗药物的敏感性，并表明神经酰胺代谢途径是抗癌药物开发的重要靶点。
In the preceding report we demonstrated that MCF-7-AdrR cells (adriamycin resistant) were insensitive to ceramide, whereas MCF-7 wild-type cells were sensitive. It was also shown that the drug resistant cells had an increased capacity to convert ceramide to glucosylceramide. Here we demonstrate that blocking the conversion of ceramide to glucosylceramide increases MCF-7-AdrR cell sensitivity to ceramide as well as to antitumor agents. Treatment of MCF-7 cells with adriamycin elicited a 5-fold increase in ceramide, and caused oligonucleosomal fragmentation, characteristic to apoptosis. Under similar treatment conditions, ceramide was not generated in MCF-7-AdrR cells. In MCF-7-AdrR cells neither C6-ceramide nor tamoxifen was cytotoxic; however, the addition of tamoxifen to the C6-ceramide treatment regimen reduced cell viability to 42% and elicited apoptosis. Treatment of MCF-7-AdrR cells with Adriamycin promoted an increase in ceramide only if tamoxifen was present, in which case ceramide increased 7-fold, and cell viability decreased to 50%. The employment of another agent, RU486 (Mifepristone), which blocks ceramide glycosylation, increased MCF-7-AdrR cell sensitivity to adriamycin in a dose-dependent manner. Our data show that agents that block ceramide glycosylation potentiate cellular sensitivity to ceramide and to chemotherapeutic drugs, and suggest that the ceramide metabolic pathway is an important target for anticancer drug development.