N-Butyldeoxynojirimycin inhibits murine melanoma cell ganglioside metabolism and delays tumor onset
N-Butyldeoxynojirimycin inhibits murine melanoma cell ganglioside metabolism and delays tumor onset
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DOI：
10.1016/s0304-3835(03)00459-2
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发表时间：
2003-11-10
期刊：
影响因子：
9.7
通讯作者：
Ladisch, S
中科院分区：
文献类型：
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作者：
Guerrera, M;Ladisch, S
异常神经节苷脂代谢与肿瘤进展有关。由于神经节苷脂耗竭降低了MEB 4小鼠黑色素瘤细胞的致瘤性，我们研究了N-丁基脱氧野尻霉素（NB-DNJ），一种口服给药的亚氨基糖，用于抑制鞘糖脂贮积病患者的葡萄糖神经酰胺（GlcCer）合酶，对MEB 4黑色素瘤细胞神经节苷脂代谢，细胞生物学和肿瘤发生的影响。我们发现50 μ M NB-DNJ降低MEB 4细胞GlcCer合成酶活性（70%）、神经节苷脂合成（61%）和脱落（37%），而神经酰胺浓度和细胞活力不受影响。部分神经节苷脂耗竭导致肿瘤发作延迟，但肿瘤发病率没有延迟，可能是因为神经节苷脂恢复迅速（48小时）。NB-DNJ处理MEB 4细胞延迟肿瘤发展为肿瘤细胞神经节苷脂代谢作为癌症治疗靶点的概念提供了进一步的支持。(C)2003爱思唯尔爱尔兰有限公司保留所有权利。
Aberrant ganglioside metabolism is linked to tumor progression. Since ganglioside depletion reduced tumorigenicity of MEB4 murine melanoma cells, we studied N-butyldeoxynojirimycin (NB-DNJ), an imino sugar administered orally to inhibit glucosylceramide (GlcCer) synthase in patients with glycosphingolipid storage diseases, for effects on MEB4 melanoma tumor cell ganglioside metabolism, cell biology, and tumorigenesis. Here we show that 50 muM NB-DNJ reduced MEB4 cell GlcCer synthase activity (by 70%), ganglioside synthesis (by 61%), and shedding (by 37%) while ceramide concentrations and cell viability were unaffected. Partial ganglioside depletion caused a delay in tumor onset but not in tumor incidence, possibly because of rapid (48 h) ganglioside recovery. The delay in tumor development by NB-DNJ treatment of MEB4 cells provides further support for the concept of tumor cell ganglioside metabolism as a therapeutic target in cancer. (C) 2003 Elsevier Ireland Ltd. All rights reserved.