Epigenetic modulators combination with chemotherapy in breast cancer cells

Abstract

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.