Epigenetic effects of the natural flavonolignan silibinin on colon adenocarcinoma cells and their derived metastatic cells

摘要

Epigenetic modifications are important in tumorigenesis. The most frequent epigenetic phenomena in cancer are histone deacetylation and DNA hypermethylation, which lead to gene silencing, particularly of tumor suppressor genes. However, monotherapies with histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors lack efficacy, hence there is a need to enhance their anticancer action in a safe and effective combination therapy. The present study investigated the epigenetic effects of the natural flavonolignan silibinin in a model of colon cancer progression, the primary adenocarcinoma cells SW480 and their derived metastatic cells SW620. Silibinin did not change the activity of HDACs, but it was able to significantly inhibit DNMT activity in both SW480 and SW620 cells. The clinically used HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), and the broad spectrum HDAC inhibitor, trichostatin A (TSA), combined with silibinin demonstrated synergistic effects on cell death induction, may be related to its DNMT inhibition properties. The present data suggest that treatments combining silibinin and HDAC inhibitors may represent a promising approach, given the non-toxic nature of silibinin and the fact that HDAC inhibitors selectively target cancer cells.