Epigenetic modulation of cancer cells by natural polyphenols and flavonoids

Introduction: A variety of natural compounds, especially polyphenols and flavonoids, display interesting beneficial physiological activities. Some specific compounds show promising chemopreventive and anticancer activities even against therapy-resistant malignancies like hepatocellular carcinomas (HCC). The aim of this study was to analyze a possible epigenetic modulation of tumor cells by particular polyphenols and flavonoids that exhibit a broad anticancer activity.

Methods: Different chemical groups of polyphenols and flavonoids were examined in silico by docking analyses, in vitro by assaying viability, proliferation and toxicity and also ex vivo by investigating the activities on human peripheral blood mononuclear cells (PBMCs) or expanded human natural killer (NK) cells. As HCC tumor models the p53 deficient cell line Hep3B and the p53 wild-type cell line HepG2 were used.

Results: We observed that the polyphenols gossypol and kaempferol, as well as the flavonoids 6- and 8-prenylnaringenin display a novel epigenetic activity by inhibiting the human histone deacetylases (HDACs). Whereas all four natural compounds are known to exert inherent anticancer activities, in depth toxicity assays revealed that gossypol has a high, kaempferol an intermediate and 6- as well as 8-prenylnaringenin a very low and therefore clinically very interesting toxicity profile.

Discussion: Our results indicate that a number of natural compounds with anticancer activities exhibit also functions of epigenetic modulators. However, only a small fraction of these compounds seems appropriate to serve as lead substances for a future clinical application in cancer therapy. Interestingly, especially the flavonoids 6- and 8-prenylnaringenin combine broad anti-tumor properties together with an extremely low toxicity on non-malignant cells and warrant further translational development.