Metabolic monosaccharides altered cell responses to anticancer drugs
Metabolic monosaccharides altered cell responses to anticancer drugs
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DOI：
10.1016/j.ejpb.2012.03.012
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Liang, Jun F.
中科院分区：
文献类型：
--
作者：
Chen, Long;Liang, Jun F.
代谢糖工程已被用于操纵细胞表面的糖化学，从而操纵细胞/细胞相互作用、细胞粘附和细胞迁移。然而，糖工程在制药科学中的潜在应用直到最近才被研究。本文报道了N-乙酰-D-甘露糖胺（ManNAc）的类似物Ac（4）ManNAc可影响细胞对抗癌药物的反应。虽然来自不同组织和器官的细胞对Ac（4）ManNAc处理的反应不同，但在对具有不同化学结构和作用机制的各种药物进行测试时，唾液酸含量增加的处理细胞显示出对抗癌药物的敏感性显著降低（高达130倍）。在Ac（4）ManNAc治疗过程中，既没有观察到P-糖蛋白活性增加，也没有观察到药物摄取减少。然而，观察到细胞内药物分布的极大改变。大多数细胞内柔红霉素被发现在核周区域，但在Ac（4）ManNAc处理的细胞中没有预期的核。由于唾液酸糖蛋白和神经节苷脂在高尔基体中合成，细胞内聚糖影响细胞内信号传导和药物分布似乎是Ac（4）ManNAc影响细胞对抗癌药物敏感性的主要原因。有趣的是发现，虽然Ac（4）ManNAc处理的乳腺癌细胞（MDA-MB-231）对5-氟尿嘧啶保持相同的敏感性，但5-氟尿嘧啶对相同的Ac（4）ManNAc处理的正常细胞（MCF-10A）的IC 50值增加了20倍以上。因此，这种Ac（4）ManNAc治疗扩大了正常细胞和肿瘤细胞之间的药物反应差异，为进一步提高抗癌药物的选择性和治疗效率提供了独特的机会。(C)2012爱思唯尔有限公司版权所有。
Metabolic glycoengineering has been used to manipulate the glycochemistry of cell surfaces and thus the cell/cell interaction, cell adhesion, and cell migration. However, potential application of glycoengineering in pharmaceutical sciences has not been studied until recently. Here, we reported that Ac(4)ManNAc, an analog of N-acetyl-D-mannosamine (ManNAc), could affect cell responses to anticancer drugs. Although cells from different tissues and organs responded to Ac(4)ManNAc treatment differently, treated cells with increased sialic acid contents showed dramatically reduced sensitivity (up to 130 times) to anti-cancer drugs as tested on various drugs with distinct chemical structures and acting mechanisms. Neither increased P-glycoprotein activity nor decreased drug uptake was observed during the course of Ac(4)ManNAc treatment. However, greatly altered intracellular drug distributions were observed. Most intracellular daunorubicin was found in the perinuclear region, but not the expected nuclei in the Ac(4)ManNAc treated cells. Since sialoglycoproteins and gangliosides were synthesized in the Golgi, intracellular glycans affected intracellular signal transduction and drug distributions seem to be the main reason for Ac(4)ManNAc affected cell sensitivity to anticancer drugs. It was interesting to find that although Ac(4)ManNAc treated breast cancer cells (MDA-MB-231) maintained the same sensitivity to 5-Fluorouracil, the IC50 value of 5-Fluorouracil to the same Ac(4)ManNAc treated normal cells (MCF-10A) was increased by more than 20 times. Thus, this Ac(4)ManNAc treatment enlarged drug response difference between normal and tumor cells provides a unique opportunity to further improve the selectivity and therapeutic efficiency of anticancer drugs. (C) 2012 Elsevier B.V. All rights reserved.