The Inhibitor of Histone Deacetylases Sodium Butyrate Enhances the Cytotoxicity of Mitomycin C
The Inhibitor of Histone Deacetylases Sodium Butyrate Enhances the Cytotoxicity of Mitomycin C
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DOI：
10.1158/1535-7163.mct-12-0193
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发表时间：
2012-10-01
影响因子：
5.7
通讯作者：
Anachkova, Boyka
中科院分区：
文献类型：
--
作者：
Gospodinov, Anastas;Popova, Stanislava;Anachkova, Boyka
组蛋白去乙酰化酶抑制剂的使用已被提出作为一种有前途的方法，以增加化疗中的DNA损伤诱导药物的细胞杀伤作用。然而，其作用的分子机制仍然研究不足。在本文中，我们评估了组蛋白去乙酰化酶抑制剂丁酸钠对交联剂丝裂霉素C诱导的DNA损伤反应的影响。丁酸钠增加丝裂霉素C的细胞毒性，但不损害修复途径所需的去除丝裂霉素C诱导的病变，既不核苷酸切除修复率也不同源重组修复率降低。丁酸钠处理废除丝裂霉素C处理的细胞中的S期细胞周期检查点，并诱导G（2）-M检查点。然而，丁酸钠单独处理导致活性氧的积累，DNA双链断裂和细胞凋亡。这些结果表明，活性氧的积累介导的DNA损伤负荷的增加可能是丁酸钠增强丝裂霉素C的细胞毒性的主要机制。Mol Cancer Ther; 11（10）; 2116-26. (C)2012年AACR。
The use of histone deacetylase inhibitors has been proposed as a promising approach to increase the cell killing effect of DNA damage-inducing drugs in chemotherapy. However, the molecular mechanism of their action remains understudied. In the present article, we have assessed the effect of the histone deacetylase inhibitor sodium butyrate on the DNA damage response induced by the crosslinking agent mitomycin C. Sodium butyrate increased mitomycin C cytotoxicity, but did not impair the repair pathways required to remove mitomycin C-induced lesions as neither the rate of nucleotide excision repair nor the homologous recombination repair rate were diminished. Sodium butyrate treatment abrogated the S-phase cell-cycle checkpoint in mitomycin C-treated cells and induced the G(2)-M checkpoint. However, sodium butyrate treatment alone resulted in accumulation of reactive oxygen species, double-strand breaks in DNA, and apoptosis. These results imply that the accumulation of reactive oxygen species-mediated increase in DNA lesion burden may be the major mechanism by which sodium butyrate enhances the cytotoxicity of mitomycin C. Mol Cancer Ther; 11(10); 2116-26. (C) 2012 AACR.