Why Do Dietary Flavonoids Have a Promising Effect as Enhancers of Anthracyclines? Hydroxyl Substituents, Bioavailability and Biological Activity.

Anthracyclines currently play a key role in the treatment of many cancers, but the limiting factor of their use is the widespread phenomenon of drug resistance and untargeted toxicity. Flavonoids have pleiotropic, beneficial effects on human health that, apart from antioxidant activity, are currently considered small molecules-starting structures for drug development and enhancers of conventional therapeutics. This paper is a review of the current and most important data on the participation of a selected series of flavonoids: chrysin, apigenin, kaempferol, quercetin and myricetin, which differ in the presence of an additional hydroxyl group, in the formation of a synergistic effect with anthracycline antibiotics. The review includes a characterization of the mechanism of action of flavonoids, as well as insight into the physicochemical parameters determining their bioavailability in vitro. The crosstalk between flavonoids and the molecular activity of anthracyclines discussed in the article covers the most important common areas of action, such as (1) disruption of DNA integrity (genotoxic effect), (2) modulation of antioxidant response pathways, and (3) inhibition of the activity of membrane proteins responsible for the active transport of drugs and xenobiotics. The increase in knowledge about the relationship between the molecular structure of flavonoids and their biological effect makes it possible to more effectively search for derivatives with a synergistic effect with anthracyclines and to develop better therapeutic strategies in the treatment of cancer.