Synergistic anti-breast cancer effect of a combined treatment with the methyl donor S-adenosyl methionine and the DNA methylation inhibitor 5-aza-2-deoxycytidine
Synergistic anti-breast cancer effect of a combined treatment with the methyl donor S-adenosyl methionine and the DNA methylation inhibitor 5-aza-2-deoxycytidine
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DOI：
10.1093/carcin/bgt284
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发表时间：
2014-01-01
期刊：
影响因子：
4.7
通讯作者：
Szyf, Moshe
中科院分区：
文献类型：
--
作者：
Chik, Flora;Machnes, Ziv;Szyf, Moshe
DNA去甲基化试剂激活肿瘤抑制基因，这些基因在癌症中被DNA甲基化沉默，因此成为一种新的癌症治疗方法。5-氮胞苷(VIDAZA)是这类药物的第一个代表，已被批准用于治疗骨髓增生异常综合征，目前正在对包括实体瘤在内的其他癌症进行测试。然而，5-氮杂胞苷或其脱氧类似物5-氮杂-2-脱氧胞苷(5-azaCDR)也可通过DNA去甲基化诱导癌前转移基因甲基化，从而诱导癌细胞侵袭。由于5-氮胞苷是一种有效的肿瘤生长抑制剂，我们测试了它与DNA甲基化试剂-甲基供体S-腺苷蛋氨酸联合使用是否能在保持其生长抑制作用的同时阻断5-氮杂胞苷的去甲基化活性。我们在这里使用了几个侵袭性和非侵袭性的乳腺癌细胞株，表明SAM抑制了5-azaCDR诱导的全局和基因特异性去甲基化，阻止了前转移基因uPA和MMP2的5-azaCDR激活，从而抑制了细胞侵袭力，同时增强了5-azaCDR的生长抑制作用及其对肿瘤抑制基因的影响。结合不同水平作用于DNA甲基化机制的药物被认为是癌症表观遗传治疗的一种新策略。
DNA-demethylating agents activate tumor suppressor genes that are silenced by DNA methylation in cancer and are therefore emerging as a novel approach to cancer therapy. 5-azacytidine (VIDAZA), the first representative of this class of drugs was approved for treatment of myelodysplastic syndromes and is currently being tested on other cancers including solid tumors. However, 5-azacytidine or its deoxy-analog, 5-aza-2-deoxycytidine (5-azaCdR) could also induce methylated prometastatic genes by DNA demethylation and induce cancer cell invasiveness. Since 5-azacytidine is a potent cancer growth inhibitor, we tested whether combining it with a DNA-methylating agent, the methyl donor S-adenosyl methionine (SAM), would block the adverse demethylating activity of 5-azaCdR while maintaining its growth suppression effects. We show here using several invasive and non-invasive breast cancer cell lines that SAM inhibits global- and gene-specific demethylation induced by 5-azaCdR, prevents 5-azaCdR activation of prometastatic genes uPA and MMP2, resulting in inhibition of cell invasiveness while augmenting the growth inhibitory effects of 5-azaCdR and its effects on tumor suppressor genes. Combination of drugs acting on the DNA methylation machinery at different levels is proposed as a new strategy for epigenetic therapy of cancer.