Suppression of the kinase activity of receptor tyrosine kinases by anthocyanin-rich mixtures extracted from bilberries and grapes.

Two standardized anthocyanin-rich mixtures were investigated for their ability to inhibit the receptor tyrosine kinases (RTKs) EGFR, ErbB2, ErbB3, VEGFR-2, and VEGFR-3. Both mixtures reduced the kinase activity of recombinant kinase domains of each RTK at concentrations <or=12.9 microg/mL, with preferential inhibition of VEGFR-2 and EGFR (<or=3.4 microg/mL). Similarly, ligand-induced autophosphorylation of these RTKs in human vulva carcinoma or porcine aortic endothelial cells was suppressed by both mixtures, with ErbB3 and VEGFR-3 being preferentially inhibited. Anthocyanin-rich extracts completely abrogated VEGFR-3 phosphorylation at concentrations of >or=50 microg/mL. These results indicate that anthocyanin-rich mixtures can inhibit RTKs with low specificity. The rank order of inhibitory efficacy against the tested RTKs in intact cells was VEGFR-3 >> VEGFR-2 > ErbB3 > EGFR > ErbB2. Considering the important role of RTKs in carcinogenesis, their inhibition by anthocyanin-rich mixtures suggests that they may serve as biomarkers of the pharmacological efficacy of anthocyanins in future chemoprevention experiments and in clinical intervention studies.