Synergistic antineoplastic action of DNA methylation inhibitor 5-aza-2'-deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
Synergistic antineoplastic action of DNA methylation inhibitor 5-aza-2'-deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
复制标题
DOI：
10.1002/ijc.10789
复制
发表时间：
2003-01-10
影响因子：
6.4
通讯作者：
Momparler, RL
中科院分区：
文献类型：
--
作者：
Primeau, M;Gagnon, J;Momparler, RL
在肿瘤发生过程中，异常的DNA甲基化和染色质结构的变化可以使癌症相关基因沉默。据报道，5-氮杂-2 '-脱氧胞苷，一种有效的DNA甲基化抑制剂，与组蛋白去乙酰化酶抑制剂组合，可以产生这些基因的协同再激活。本研究的目的是研究5-氮杂-2 '-脱氧胞苷与一种有效的组蛋白去乙酰化酶抑制剂缩酚酸肽（depsipeptide）联合应用对人乳腺癌细胞系MDA-MB-231和MDA-MB-435的体外杀伤活性。我们观察到5-氮杂-2 '-脱氧胞苷和缩肽的组合与单独施用的任一种药剂相比产生了针对这些肿瘤细胞的协同抗肿瘤作用。我们还研究了这种药物组合对maspin和凝溶胶蛋白表达激活的影响。据报道，这两个基因的功能是抑制肿瘤转移，在乳腺癌中被表观遗传事件沉默。使用半定量RT-PCR，我们观察到5-氮杂-2 '-脱氧胞苷与缩肽的组合与单独的每种试剂相比产生了更大的maspin和凝溶胶蛋白的再活化。5-氮杂-2 '-脱氧胞苷和缩肽对乳腺癌细胞系的协同相互作用为在未来的晚期乳腺癌患者临床试验中研究这种有趣的药物组合提供了理论基础。(C)2002 Wiley-Liss，Inc.
During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2'-deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2'-deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2'-deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2'-deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2'-deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer. (C) 2002 Wiley-Liss, Inc.