title: Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism.
abstract: OBJECTIVE
  Urolithins, metabolites produced by the gut microbiota from ellagic acid, have been acknowledged with cancer chemopreventive activity. Although urolithin A (Uro-A) has been reported to be the most active one, 10-50 % of humans can also produce the isomer isourolithin A (IsoUro-A). However, no biological activity for IsoUro-A has been reported so far. Herein, we describe for the first time the antiproliferative effect of IsoUro-A, compared to Uro-A, against both human colon cancer (Caco-2) and normal (CCD18-Co) cell lines.
  
  
  METHODS
  Cell proliferation was evaluated by MTT and Trypan blue exclusion assays. Cell cycle was analyzed by flow cytometry and apoptosis measured by the Annexin V/PI method. Finally, urolithins metabolism was analyzed by HPLC-DAD-MS/MS.
  
  
  RESULTS
  IsoUro-A inhibited the proliferation of Caco-2 cells in a time- and dose-dependent manner, though it was significantly lower than Uro-A (IC50= 69.7 ± 4.5 and 49.2 ± 3.8 μM at 48 h, respectively). Both urolithins arrested Caco-2 cell cycle at S and G2/M phases and induced apoptosis at concentrations previously found in human colon tissues. Notably, Caco-2 cells glucuronidated more efficiently IsoUro-A than Uro-A (~50 vs. ~20 % of conversion after 48 h, respectively). Both Uro-A and IsoUro-A glucuronides did not exert antiproliferative effects. In addition, cell growth inhibition was higher in Caco-2 than in normal cells.
  
  
  CONCLUSIONS
  IsoUro-A exerts strong antiproliferative activity, which is reduced by the extensive glucuronidation at 9-position in cancer cells. Further studies are needed to elucidate whether the in vitro structure-activity relationship found for Uro-A and IsoUro-A plays any role in humans.
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100, Murcia, Spain. agsarrias@cebas.csic.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Sarrías
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100, Murcia, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Núñez-Sánchez
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100, Murcia, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Villalba
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100, Murcia, Spain.
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Tomás-Barberán
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Campus de Espinardo, P.O. Box 164, 30100, Murcia, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Espín
mesh_terms: D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003106:Colon / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003374:Coumarins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D016195:G2 Phase; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007536:Isomerism; D007700:Kinetics; D015394:Molecular Structure; D016196:S Phase
chemical_list: D016588:Anticarcinogenic Agents; D015415:Biomarkers; D003374:Coumarins; D020719:Glucuronides; C000621704:isourolithin A; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
keywords: Apoptosis; Cell cycle; Colon cancer; Ellagic acid; Isourolithin A; Urolithins