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.
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ABSTRACT: Red grape pomace extract (oenocyanin) is a cheap and rich source of anthocyanins, the agents suggested to possess cancer chemopreventive properties. Here the hypothesis was tested that oenocyanin added to the diet can interfere with intestinal adenoma development in the Apc(Min) mouse, a model of intestinal carcinogenesis linked to an Apc mutation.
Mice received oenocyanin (0.3%) in their diet until week 16, when adenoma number and burden were recorded. Expression of Akt and ERK proteins was studied by Western blot in adenomas to discover effects of anthocyanins on cellular signalling via the PI3 and MAP kinase pathways. Levels of anthocyanins were measured by HPLC with visible spectroscopic or mass spectrometric detection.
In mice which had consumed oenocyanin, overall adenoma burden was halved and adenoma number was marginally reduced when compared with mice on control diet. The proliferation index in colonic adenomatous crypts, as reflected by Ki-67 staining, was significantly decreased from 88.14% in control mice to 75.6+/-4% in mice on oenocyanin (P=0.014). Expression of Akt in small intestinal adenomas from Apc(Min) mice on oenocyanin was reduced by 54% (P=0.003), when compared to controls. Oenocyanin anthocyanins and glucuronide metabolites were found in the urine and intestine but not in plasma.
The results suggest that oenocyanin may be a viable and economical alternative to anthocyanin-rich berry extracts for chemopreventive intervention. Akt and pErk might be suitable biomarkers of anthocyanin target organ efficacy.
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ABSTRACT: Cell signaling pathways play fundamental roles in modulating various biological processes such as cell cycle, cell proliferation,
differentiation, and survival. The abnormal activation of several signaling pathways has been linked to the development of
various cancers, whereas the inhibition of these pathways has also been considered as a strategy for cancer prevention and
therapy. A series of in vitro studies have shown that berry extracts may exert their chemopreventive effects through targeting
different cellular signaling pathways, including transcription factors (NFκB, AP-1), their upstream kinases (RTKs, PI3K/Akt,
MAPKs), and their downstream target genes (COX-2, VEGF). This chapter outlined the current progresses in this research area.
It should be noted that more efforts are needed to address the direct targets of berry extracts and their active compounds,
as well as the crosstalk among the various pathways that are inhibited for chemopreventive effects by the berries and berry
components because of the complexity and diversity of cancers, cell signaling pathways, and extracts themselves.
KeywordsBerry extracts-Signaling pathways-Cellular transformation
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