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    Epigenetic modulators combination with chemotherapy in breast cancer cells
    (Wiley, 2021) Arı, Ferda; Napieralski, Rudolf; Akgün, Oğuzhan; Magdolen, Viktor; Ulukaya, Engin
    Despite the concerning adverse effects on tumour development, epigenetic drugsare very promising in cancer treatment. The aim of this study was to compare the dif-ferential effects of standard chemotherapy regimens (FEC: 5-fluorouracil plus epi-rubicine plus cyclophosphamide) in combination with epigenetic modulators(decitabine, valproic acid): (a) on gene methylation levels of selected tumour bio-markers (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 aschanges concerning the invasion capacity were monitored in cell culture models ofbreast cancer (MCF-7, MDA-MB-231). A significant overall decrease of cell survivalwas observed in the FEC-containing combination therapies for both cell lines. Meth-ylation results showed a general tendency towards increased demethylation of theuPA and PAI-1 gene promoters for the MCF-7 cells, as well as the proapoptoticDAPK gene in the treatment regimens for both cell lines. The uPA and PAI-1 antigenlevels were mainly increased in the supernatant of FEC-only treated MDA-MB-231cells. DAC-only treatment induced an increase of secreted uPA protein in MCF-7 cellculture, while most of the VPA-containing regimens also induced uPA and PAI-1expression in MCF-7 cell fractions. Epigenetically active substances can also induce are-differentiation in tumour cells, as shown by 5meC, H3K27me3 applying ICC.Significance of the study: Epigenetic modulators especially in the highlyundifferentiated and highly malignant MDA-MB-231 tumour cells significantlyreduced tumour malignancy thus; further clinical studies applying specific combina-tion therapies with epigenetic modulators may be warranted.