Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells
Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells
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DOI：
10.1158/1535-7163.mct-13-0137
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发表时间：
2013-10-01
影响因子：
5.7
通讯作者：
Bitzer, Michael
中科院分区：
文献类型：
--
作者：
Venturelli, Sascha;Berger, Alexander;Bitzer, Michael
表观遗传改变是癌症的一个标志，它控制着基因的沉默。到目前为止，5-氮杂胞苷（5-aza-CR，Vidaza）和5-氮杂-2 '-脱氧胞苷（5-aza-dC，Dacogen）是临床上唯一批准的DNA甲基转移酶抑制剂（DNMTi）。目前的努力试图开发DNMTi应用超出急性白血病或骨髓增生异常综合征，特别是实体瘤。尽管这两种药物的结构差异很小，但它们触发了不同的分子机制，这些机制与合理选择新的联合疗法高度相关。因此，我们在体外研究了人肝癌、结肠癌、肾癌和肺癌细胞的细胞死亡途径，在体内研究了绒毛尿囊膜和异种移植模型的细胞死亡途径。实时癌细胞监测和细胞因子分析揭示了对两种药物的截然不同的反应模式。5-aza-dC诱导p53依赖性肿瘤细胞衰老和大量DNA双链断裂。相反，5-aza-CR下调p53，诱导caspase激活和凋亡。这些肿瘤细胞的个体反应模式可以在绒毛尿囊膜试验和肝癌异种移植模型中在体内得到验证。虽然5-aza-CR和5-aza-dC被认为是具有相似治疗活性的药物，但它们在肿瘤细胞中诱导不同的分子反应。这些发现以及其他报道的差异使得能够并促进新的联合策略的合理设计，以进一步利用这两种药物在临床肿瘤学不同领域的表观遗传作用模式。(c)2013年AACR。
Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2 '-deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology. (c) 2013 AACR.