Inhibition of cancer cell proliferation by 5-fluoro-2'-deoxycytidine, a DNA methylation inhibitor, through activation of DNA damage response pathway.
Inhibition of cancer cell proliferation by 5-fluoro-2'-deoxycytidine, a DNA methylation inhibitor, through activation of DNA damage response pathway.
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DOI：
10.1186/2193-1801-1-65
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Wu M
中科院分区：
文献类型：
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作者：
Zhao Q;Fan J;Hong W;Li L;Wu M
在肿瘤发生过程中发生了多种表观遗传变化，包括DNA甲基化的改变。已经开发了各种DNA甲基化的抑制剂来防止癌细胞的增殖。5-氟-2 ′-脱氧胞苷（FCdR）就是这样一种DNA甲基化抑制剂，目前正处于II期临床试验阶段。为了研究FCdR可能介导肿瘤细胞增殖抑制的分子机制，我们分析了FCdR在从不同肉瘤建立的各种细胞系中的毒性。我们发现结肠癌细胞系HCT 116对FCdR的敏感性比其他细胞高得多。FCdR处理抑制HCT 116细胞在G2/M检查点，并上调多个癌症相关基因的表达，这可能是由于其对DNA甲基化的抑制活性。此外，我们发现FCdR激活DNA损伤反应途径。使用ATM和ATR激酶活性的抑制剂，这是放大DNA损伤修复信号所需的，我们表明，FCdR诱导的抑制HCT 116细胞在G2/M是通过激活DNA损伤反应途径介导的。本文的在线版本（doi：10.1186/2193-1801-1-65）包含补充材料，可供授权用户使用。
Multiple epigenetic changes, including alterations in DNA methylation occur during tumorigenesis. Various inhibitors of DNA methylation have been developed to prevent proliferation of cancer cells. 5-fluoro-2′-deoxycytidine (FCdR) is one such DNA methylation inhibitor, which is currently in phase II clinical trial. To investigate the molecular mechanism/s by which FCdR might mediate repression of tumor cell proliferation, we analyzed the toxicity of FCdR in various cell lines established from different sarcomas. We found HCT116, a colon cancer cell line, is much more sensitive to FCdR compared to others. FCdR treatment inhibited HCT116 cells at G2/M check point and up-regulated expression of multiple cancer-related genes, which could be due to its inhibitory activity towards DNA methylation. Furthermore, we found that FCdR activates DNA damage response pathway. Using an inhibitor for ATM and ATR kinases activity, which are required for amplifying the DNA damage repair signal, we show that FCdR induced inhibition of HCT116 cells at G2/M is mediated through activation of DNA damage response pathway. The online version of this article (doi:10.1186/2193-1801-1-65) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1038/nrm2450
发表时间：
2008-08
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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