title: The ellagitannin colonic metabolite urolithin D selectively inhibits EphA2 phosphorylation in prostate cancer cells.
abstract: METHODS
  The Eph-ephrin system comprises emerging proteins involved in many pathophysiological processes. The pharmacological activity of the main metabolites derived from the intake of some classes of (poly)phenolic compounds, such as caffeoylquinic acids, flavan-3-ols, and ellagitannins, on the Eph-ephrin interaction was evaluated at physiological concentrations. Functional studies to elucidate their role in prostate cancer were also performed.
  
  
  RESULTS
  Among the 21 phenolics screened by an ELISA-binding assay, just urolithin C, urolithin D, and ellagic acid succeeded to inhibit the EphA2-ephrin-A1 binding. Urolithin D, the most active, was a competitive and reversible antagonist of EphA receptors able to discriminate between EphA and EphB receptors, showing intra-classes selectivity. Molecular modeling and structure-activity relationships shed light on the binding mode and selective activity of urolithin D. This catabolite blocked EphA2 phosphorylation mediated by ephrin-A1, while lacking cytotoxicity and anti-proliferative effects, and was inactive on the EphA2 kinase assay.
  
  
  CONCLUSIONS
  The mechanisms behind the cancer preventive properties of foods rich in flavan-3-ols and caffeoylquinic acids are not associated with metabolic pathways directly linked to the Eph-ephrin system. However, the ellagitannin-derived colonic metabolite urolithin D was able to exert remarkable and selective EphA-ephrin-A inhibition, which might impact on prostate cancer prevention.
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Carmine
authors: C
authors: Giorgio
authors: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, Via Volturno, Parma, Italy.
authors: Pedro
authors: P
authors: Mena
authors: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, Via Volturno, Parma, Italy.
authors: Daniele
authors: D
authors: Del Rio
authors: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, Via Volturno, Parma, Italy.
authors: Furio
authors: F
authors: Brighenti
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Elisabetta
authors: E
authors: Barocelli
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Iftiin
authors: I
authors: Hassan-Mohamed
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Donatella
authors: D
authors: Callegari
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Alessio
authors: A
authors: Lodola
authors: Department of Pharmacy, University of Parma, Parma, Italy.
authors: Massimiliano
authors: M
authors: Tognolini
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D003374:Coumarins; D047348:Hydrolyzable Tannins; C013515:ellagitannin; C000595063:urolithin D; D036104:Receptor, EphA2
keywords: Colonic metabolites; Dietary (poly)phenols; Eph/ephrin; Human microbiome; Urolithins