Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism

卷:56

Gonzalez-Sarrias, Antonio ; Angeles Nunez-Sanchez, Maria ; Garcia-Villalba, Rocio ; Tomas-Barberan, Francisco A. ; Carlos Espin, Juan

CSIC, Dept Food Sci & Technol

关键词: Urolithins;    Isourolithin A;    Ellagic acid;    Cell cycle;    Apoptosis;    Colon cancer;   

DOI  :  10.1007/s00394-015-1131-7

学科分类：食品科学和技术

【 摘 要 】

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. 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. 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 mu M at 48 h, respectively). Both urolithins arrested Caco-2 cell cycle at S and G(2)/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 (similar to 50 vs. similar to 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. 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.