Dietary polyphenols for managing cancers: What have we ignored?

Although the chemoprevention and anti-cancer activities of dietary polyphenols have been evidenced through both in vitro and in vivo studies, most of the human clinical trials were unsuccessful or even harmful. Debates on the beneficial roles of dietary polyphenols in cancer therapy are increasing. Many dietary polyphenols studies are conducted by in vitro experiments, but the nature of these studies does not consider the complexity of metabolic processes that are present in vivo. These can often cause instability in the dietary polyphenols, thereby leading to unsuccessful extrapolation into animal or human studies. Dietary polyphenols often have low bioavailability, which is mainly due to poor bioaccessibility and significant metabolism mediated by both host enzymes and colon microbiota. Some metabolites or catabolites are more potent and absorb better than the parent component. It is recognised that the oral bioavailability of dietary polyphenols is underestimated when the bioactive metabolites or catabolites are not considered. Notably, dietary polyphenols and their metabolites undergo further cellular metabolism within the cancer cells, which confers ``cellular bioavailability'' as an additional step to influence the actions of dietary polyphenols. Moreover, there are growing controversies in using dietary polyphenols for both chemopreventive and anti-cancer applications. A clear therapeutic window for dietary polyphenols as specific chemopreventive or chemotherapeutic agents is required. This review, thus, aims to identify key issues that were ignored by most of the studies, or are critical for future investigation.