Effects of berries on the RTK pathways and their chemoprevention


Although large numbers of studies have reported that RTKs are important in carcinogenesis, the research on the potential of targeting RTKs by berry extracts is still in its early stages.Mirtocyan is a standardized anthocyanin-rich extract of bilberries.

Both mirtocyan and oenocyanin E163, an extract of red grape pomace, can inhibit the kinase activity of recombinant kinase domains of each RTK at concentrations smaller or equal to 12.9 micro g/ml, with preferential inhibition of VEGFR-2 and EGFR.

Similarly, ligand-induced autophosphorylation of these RTKs in human vulva carcinoma or porcine aortic endothelial cells is suppressed by the mixtures. Such anthocyanin-rich extracts completely abrogate VEGFR-3 phosphorylation at concentrations of about 50 micro g/ml.

These mixtures can inhibit RTKs with low specificity. Different VEGFRs are key modulators of angiogenesis. After binding to VEGF, VEGFRs further activate intracellular signaling pathways, eliciting angiogenesis by inducing the migration and proliferation of endothelial cells.

Among six contents, delphinidin is the most effective in inhibiting the differentiation of endothelial cells. Delphinidin can also potently inhibit VEGF-induced capillarylike structure formation and endothelial cell migration in vitro.

Delphinidin inhibits VEGF-induced phosphorylation of VEGFR-2 and ERK1/2, a substrate of VEGFR-2, which may be involved in VEGF-induced endothelial cell migration and capillary-like structure formation.

Delphinidin can be not only a potent inhibitor of VEGFinduced capillary-like structure formation and endothelial cells migration, but also an inhibitor of smooth muscle cells (SMCs) migration, which is important for the mature and normal function of vasculature.

Delphinidin is shown to inhibit PDGF-induced migration of SMCs, as well as the differentiation and stabilization of endothelial cells (ECs) and SMCs into capillary-like tubular structures.

Such effects of delphinidin may be related to its inhibitory effects on PDGFR-B, which in turn leads to the inhibition of ERK1/2 activation and the chemotactic motility of SMCs . Similarly, delphinidin is an effective inhibitor of EGFR signaling, which mediates the suppression of PI3K, AKT, and MAPK. This inhibition is thought to be responsible for its inhibitory effects on the invasion, growth, and induction of apoptosis in breast cancer cells.

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