The anthocyanidins cyanidin and delphinidin are potent inhibitors of the epidermal growth-factor receptor

The aglycons of the most abundant anthocyanins in food, cyanidin (cy) and delphinidin (del), were found to inhibit the growth of human tumor cells in vitro in the micromolar range, whereas malvidin (mv), a typical anthocyanidin in grapes, was less active. The aglycons preferentially inhibited the growth of the human vulva carcinoma cell line A431, overexpressing the epidermal growth-factor receptor (EGFR). The glycosides cyanidin-3-beta-D-galactoside (cy-3-gal, idaein) and malvidin-3-beta-D-glucoside (mv-3-glc, oenin) did not affect tumor cell growth up to 100 microM. The tyrosine kinase activity of the EGFR, isolated from A431 cells, was potently inhibited by cy and del. Mv and the glycosides cy-3-gal and mv-3-glc were inactive up to 100 microM. In intact cells the influence of anthocyanin treatment on downstream signaling cascades was investigated by measuring the phosphorylation of the transcription factor Elk-1. A431 cells were transiently transfected with a luciferase reporter gene construct whose expression is controlled by MAP kinase pathway dependent phosphorylation of a GAL4-Elk-1 fusion protein. We found that cy and del inhibited the activation of the GAL4-Elk-1 fusion protein in the concentration range where growth inhibition was observed. Thus, the anthocyanidins cy and del are potent inhibitors of the EGFR, shutting off downstream signaling cascades. These effects might contribute substantially to the growth-inhibitory properties of these natural food constituents.