Despite the concerning adverse effects on tumour development, epigenetic drugs are very promising in cancer treatment. The aim of this study was to compare the differential effects of standard chemotherapy regimens (FEC: 5-fluorouracil plus epirubicine plus cyclophosphamide) in combination with epigenetic modulators (decitabine, valproic acid): (a) on gene methylation levels of selected tumour biomarkers (LINE-1, uPA, PAI-1, DAPK); (b) their expression status (uPA and PAI-1); (c) differentiation status (5meC and H3K27me3). Furthermore, cell survival as well as changes concerning the invasion capacity were monitored in cell culture models of breast cancer (MCF-7, MDA-MB-231). A significant overall decrease of cell survival was observed in the FEC-containing combination therapies for both cell lines. Methylation results showed a general tendency towards increased demethylation of the uPA and PAI-1 gene promoters for the MCF-7 cells, as well as the proapoptotic DAPK gene in the treatment regimens for both cell lines. The uPA and PAI-1 antigen levels were mainly increased in the supernatant of FEC-only treated MDA-MB-231 cells. DAC-only treatment induced an increase of secreted uPA protein in MCF-7 cell culture, while most of the VPA-containing regimens also induced uPA and PAI-1 expression in MCF-7 cell fractions. Epigenetically active substances can also induce a re-differentiation in tumour cells, as shown by 5meC, H3K27me3 applying ICC.

中文翻译：

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表观遗传调节剂与乳腺癌细胞化疗的结合

尽管对肿瘤发展有不利影响，但表观遗传药物在癌症治疗中非常有前途。本研究的目的是比较标准化疗方案（FEC：5-氟尿嘧啶加表柔比星加环磷酰胺）联合表观遗传调节剂（地西他滨、丙戊酸）的不同效果：（a）对选定肿瘤生物标志物的基因甲基化水平（ LINE-1、uPA、PAI-1、DAPK）；(b) 它们的表达状态（uPA 和 PAI-1）；(c) 分化状态（5meC 和 H3K27me3）。此外，在乳腺癌细胞培养模型（MCF-7、MDA-MB-231）中监测细胞存活率以及有关侵袭能力的变化。在两种细胞系的含 FEC 联合疗法中观察到细胞存活率总体显着降低。甲基化结果显示，在两种细胞系的治疗方案中，MCF-7 细胞的 uPA 和 PAI-1 基因启动子以及促凋亡 DAPK 基因的去甲基化都有增加的趋势。uPA 和 PAI-1 抗原水平主要在仅 FEC 处理的 MDA-MB-231 细胞的上清液中增加。仅 DAC 处理诱导 MCF-7 细胞培养物中分泌的 uPA 蛋白增加，而大多数含 VPA 的方案也诱导 MCF-7 细胞组分中的 uPA 和 PAI-1 表达。表观遗传活性物质还可以诱导肿瘤细胞的再分化，如应用 ICC 的 5meC、H3K27me3 所示。uPA 和 PAI-1 抗原水平主要在仅 FEC 处理的 MDA-MB-231 细胞的上清液中增加。仅 DAC 处理诱导 MCF-7 细胞培养物中分泌的 uPA 蛋白增加，而大多数含 VPA 的方案也诱导 MCF-7 细胞组分中的 uPA 和 PAI-1 表达。表观遗传活性物质还可以诱导肿瘤细胞的再分化，如应用 ICC 的 5meC、H3K27me3 所示。uPA 和 PAI-1 抗原水平主要在仅 FEC 处理的 MDA-MB-231 细胞的上清液中增加。仅 DAC 处理诱导 MCF-7 细胞培养物中分泌的 uPA 蛋白增加，而大多数含 VPA 的方案也诱导 MCF-7 细胞组分中的 uPA 和 PAI-1 表达。表观遗传活性物质还可以诱导肿瘤细胞的再分化，如应用 ICC 的 5meC、H3K27me3 所示。