title: Resveratrol 3-O-D-glucuronide and resveratrol 4'-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest.
abstract: METHODS
  Resveratrol is a plant-derived polyphenol with chemotherapeutic properties in animal cancer models and many biochemical effects in vitro. Its bioavailability is low and raises the possibility that the metabolites of resveratrol have biological effects. Here we investigate the actions of resveratrol 3-O-D-glucuronide, resveratrol 4-O-D-glucuronide, and resveratrol 3-O-Dsulfate on the growth of colon cancer cells in vitro.
  
  
  RESULTS
  The growth of Caco-2, HCT-116, and CCL-228 cells was measured using the neutral red and MTT assays. Resveratrol and each metabolite inhibited cell growth with IC50 values of 9.8–31 μM. Resveratrol caused S phase arrest in all three cell lines. Resveratrol 3-O-D-glucuronide and resveratrol 4-O-D-glucuronide caused G1 arrest in CCL-228 and Caco-2 cells. Resveratrol 3-O-D-sulfate had no effect on cell cycle. Growth inhibition was reversed by an inhibitor of AMP-activated protein kinase (compound C) or an adenosine A3 receptor antagonist (MRS1191). The A3 receptor agonist 2Cl-IB-MECA inhibited growth and A3 receptors were detected in all cell lines. The resveratrol glucuronides also reduced cyclin D1 levels but at higher concentrations than in growth experiments and generally did not increase phosphorylated AMP-activated protein kinase.
  
  
  CONCLUSIONS
  Resveratrol glucuronides inhibit cell growth by G1 arrest and cyclin D1 depletion, and our results strongly suggest a role for A3 adenosine receptors in this inhibition.
authors: School of Pharmacy and Chemistry, Kingston University, Kingston upon Thames, UK.
authors: Elena
authors: E
authors: Polycarpou
authors: Lisiane B
authors: LB
authors: Meira
authors: Simon
authors: S
authors: Carrington
authors: Elizabeth
authors: E
authors: Tyrrell
authors: Helmout
authors: H
authors: Modjtahedi
authors: Mark A
authors: MA
authors: Carew
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D058918:Adenosine A3 Receptor Antagonists; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D020719:Glucuronides / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; C530104:CCND1 protein, human; D020719:Glucuronides; D043684:Receptor, Adenosine A3; D013267:Stilbenes; C499731:resveratrol-4'-O-glucuronide; D019938:Cyclin D1; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol
keywords: Cell cycle; Colon cancer; Glucuronide metabolites; Resveratrol; Sulfate metabolites