The epidermal growth factor receptor and human topoisomerases represent potential cellular targets of oligomeric procyanidins

Abstract

Oligomeric procyanidins were found to inhibit the protein tyrosine kinase activity of the epidermal growth factor receptor (EGFR). The inhibitory potency was found to increase with the degree of oligomerisation (PA2 > PC1 >> PB1 = PB2 = PB3 = PB4 >> (-)-epicatechin). To address the question whether the interference with the activity of isolated EGFR preparations also plays a role within intact cells, effects on the phosphorylation status of the EGFR, as a measure of its activity, were determined in human colon carcinoma cells. Treatment of HT29 cells with the trimeric procyanidin PC1 resulted in a decrease of the EGFR autophosphorylation already at low micromolar concentrations. A respective procyanidin tetramer (PA2) failed to affect substantially the receptor phosphorylation status by up to 50 microM, indicating that the effectiveness of oligomeric procyanidins against EGFR activity within intact cells might be limited with increasing degree of polymerisation. Nevertheless, oligomeric procyanidins were identified as potential inhibitors of the EGFR, which might be of interest with respect to chemoprevention. However, PC1 and PA2 were also identified as potent inhibitors of the catalytic activity of human topoisomerase I and II, demanding further studies to elucidate whether the interference of procyanidins with topoisomerases might impair DNA integrity, thus limiting their usefulness in terms of chemoprevention.

Proanthocyanidins and the risk of colorectal cancer in Italy

“…This observation, together with various studies in vitro and in vivo suggesting that chemopreventive properties mostly act on the intestinal tract [18][19][20][21]23], supports the hypothesis of a favorable effect of proanthocyanidins against colorectal cancer. Moreover, oligomeric procyanidins were found to inhibit the protein tyrosine kinase activity of the epidermal factor receptor, and this activity, together with other antioxidant properties, was found to increase with the degree of oligomerisation in the colon [17,44,45]. This is in line with our observation of a stronger effect against colorectal cancer from the proanthocyanidins with higher degree of polymerization.…”

Wine Flavonoids in Health and Disease Prevention

“…Relative inhibitory activity was primarily related to the number of phenolic hydroxyl groups (galloyl moieties) found in the active structures, with more groups generally conferring increased effect. More recent studies have observed the same trend [ 143 ]. An interesting study has focused on polyphenol structural elements that rules the mechanism by which polyphenols interact with topoisomerase II [ 144 ].…”

Anthocyanin‐rich extracts suppress the DNA‐damaging effects of topoisomerase poisons in human colon cancer cells

“…In contrast, extracts containing complex polyphenolic mixtures were found to potently affect the topoisomerase activity implicating a contribution of yet unknown constituents, or synergistic or additive effects. One may speculate that oligomeric and/or polymeric procyanidins contained in berries and grapes might have contributed to the modulation of topoisomerase activity by the extracts observed here, because some procyanidins have been previously characterized as topoisomerase inhibitors [12,33,34].…”