Polyphenol rich botanicals used as food supplements interfere with EphA2–ephrinA1 system

Mohamed, Iftiin Hassan; Giorgio, Carmine; Bruni, Renato; Flammini, Lisa; Barocelli, Elisabetta; Rossi, Damiano; Domenichini, Giuseppe; Poli, Ferruccio; Tognolini, Massimiliano

doi:10.1016/j.phrs.2011.06.008

Cited by 20 publications

(19 citation statements)

References 42 publications

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“…These results suggest that other mechanisms might be responsible for the inhibition of EphA2 phosphorylation by EGCG reported in a previous study [44]. In addition, the very low activity of EGCG in ELISAs measuring inhibition of Eph receptor-ephrin binding suggests that other green tea catechins may be responsible for the recently reported ability of green tea extracts to inhibit EphA2-ephrin binding [42]. …”

Section: Discussionsupporting

confidence: 62%

“…These include: (i) salycilic acid derivatives, which inhibit ligand binding to a subset of Eph receptors through non-classical mechanisms [26,38,39]; (ii) the bile acid lithocolic acid, a competitive reversible inhibitor that targets all the Eph receptors [40], and (iii) cholanic acid, which is related to lithocolic acid but shows some preference for the EphA compared to the EphB receptor class [41]. A number of plant extracts rich in polyphenols, including a green tea extract, and several polyphenol catabolites were also recently found to inhibit ephrin binding to the EphA2 receptor in vitro and ephrin-induced EphA2 tyrosine phosphorylation in PC3 prostate cancer cells [42,43]. In addition, EGCG was shown to inhibit ephrin-A1-induced EphA2 phosphorylation in human umbilical vein endothelial cells (HUVECs) and capillary-like tube formation through a mechanism that was not elucidated [44].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Noberini

Koolpe

Lamberto

et al. 2012

Pharmacological Research

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Tea contains a variety of bioactive chemicals, such as catechins and other polyphenols. These compounds are thought to be responsible for the health benefits of tea consumption by affecting the function of many cellular targets, not all of which have been identified. In a high-throughput screen for small molecule antagonists of the EphA4 receptor tyrosine kinase, we identified five tea polyphenols that substantially inhibit EphA4 binding to a synthetic peptide ligand. Further characterization of theaflavin monogallates from black tea and epigallocatechin-3,5-digallate from green tea revealed that these compounds at low micromolar concentrations also inhibit binding of the natural ephrin ligands to EphA4 and several other Eph receptors in in vitro assays. The compounds behave as competitive EphA4 antagonists, and their inhibitory activity is affected by amino acid mutations within the ephrin binding pocket of EphA4. In contrast, the major green tea catechin, epigallocatechin-3-gallate (EGCG), does not appear to be an effective Eph receptor antagonist. In cell culture assays, theaflavin monogallates and epigallocatechin-3,5-digallate inhibit ephrin-induced tyrosine phosphorylation (activation) of Eph receptors and endothelial capillary-like tube formation. However, the wider spectrum of Eph receptors affected by the tea derivatives in cells suggests additional mechanisms of inhibition besides interfering with ephrin binding. These results show that tea polyphenols derived from both black and green tea can suppress the biological activities of Eph receptors. Thus, the Eph receptor tyrosine kinase family represents an important class of targets for tea-derived phytochemicals.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Noberini

Koolpe

Lamberto

et al. 2012

Pharmacological Research

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“…[54] Briefly, compounds (Table 1) were stocked as 20 mM solutions in dimethyl sulfoxide (DMSO) and tested both in displacing and saturation studies, starting from a concentration of 200 μM. Ninety-six well ELISA high binding plates (Costar #2592) were incubated overnight at 4°C with 100 μl/well of 1 μg/ml EphA2-Fc (R&D 639-A2) diluted in sterile phosphate buffered saline (PBS, 0.2 g/l KCl, 8.0 g/l NaCl, 0.2 KH 2 PO 4 , 1.15 g/l Na 2 HPO 4 , pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Structure–Activity Relationships and Mechanism of Action of Eph–ephrin Antagonists: Interaction of Cholanic Acid with the EphA2 Receptor

et al. 2012

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The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-α-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions.

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“…42 In conclusion, previous research has investigated the effects of phytochemicals on the EphA2−ephrinA1 protein−protein interaction. 15 However, as stated in the Introduction, (poly)-phenols are metabolized/catabolized after ingestion by humans, with most being degraded to simple phenolic acids by the action of the colonic microbiota. To our knowledge, this is the first study describing the effects of (poly)phenol colonic catabolites in this system.…”

Section: Journal Of Agricultural and Food Chemistrymentioning

confidence: 99%

Perturbation of the EphA2–EphrinA1 System in Human Prostate Cancer Cells by Colonic (Poly)phenol Catabolites

Tognolini

Giorgio

Mohamed

et al. 2012

J. Agric. Food Chem.

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The Eph tyrosine kinase receptors and their ephrin ligands play a central role in human cancer as their deregulated expression induces tumorigenesis with aggressive phenotypes. To evaluate their potential contribution to EphA2-ephrinA1 modulation, several colonic catabolites of dietary (poly)phenolics, known to be generated in vivo, were screened using an ELISA-based binding assay. Some of the catabolites inhibited the binding in a dose-dependent manner (IC(50) values from 0.26 to 43 μM). Functional studies on prostate adenocarcinoma cells revealed that pyrogallol and protocatechuic acid specifically antagonized ephrinA1-Fc-induced EphA2 phosphorylation at concentrations that were not cytotoxic. The active concentrations of pyrogallol appear to be close to what can be reached in vivo under physiological conditions. Finally, because of the roles played by the Eph-ephrin system not only in cancer development but also in neurodegeneration and diabetes, pyrogallol and protocatechuic acid are candidates for more detailed functional studies to elucidate their role in these pathophysiological processes.

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Polyphenol rich botanicals used as food supplements interfere with EphA2–ephrinA1 system

Cited by 20 publications

References 42 publications

Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Structure–Activity Relationships and Mechanism of Action of Eph–ephrin Antagonists: Interaction of Cholanic Acid with the EphA2 Receptor

Perturbation of the EphA2–EphrinA1 System in Human Prostate Cancer Cells by Colonic (Poly)phenol Catabolites

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