Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells.

Flavonoids (FVs) are an important class of plant compounds postulated to be one of the constituents responsible for the beneficial effects of fruits and vegetables on health, including heart disease and cancer. At pharmacological levels, various naturally-occurring flavonoids have been shown to be cancer-protective in a variety of animal models and flavonoid derivatives, such as flavopyridol, are being assessed as chemotherapy drugs in clinical trials. This report has investigated the effects of the most common dietary FVs on several major signalling pathways in biopsies of human epithelial cells using primary cultures freshly isolated from biopsies and has obtained evidence for the previously unrecognised importance of stress kinase responses induced by kaempferol (KF), apigenin (AP) and luteolin (LU). KF, AP and LU all activated ATM/ATR (mutated in ataxia-telangiectasia and related) kinases and the p38 stress kinase and this was associated with induction of GADD45 and cell cycle arrest in G2, but not induction of apoptosis. These effects were not due to general toxicity since they were reversible on removal of FV. The inductions of ATM/ATR and p38 were functionally important since caffeine, an inhibitor of ATM/ATR, and the p38-specific inhibitor, SB203580, prevented induction of GADD45 and growth arrest by these three flavonoids. In contrast, although quercetin (QU) activated ATM (but not ATR), it did not activate p38 kinase, GADD45 or p53. QU may interfere with one of the lipoxygenase (LOX) pathways since the growth inhibitory effects of QU (but not the other three flavonoids) could be reversed by addition of LOX metabolites, particularly 12- and 15-hydroxyeicostetraenic acids.