期刊
EUROPEAN JOURNAL OF NUTRITION
卷 56, 期 2, 页码 831-841出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00394-015-1131-7
关键词
Urolithins; Isourolithin A; Ellagic acid; Cell cycle; Apoptosis; Colon cancer
资金
- MINECO, Spain [CICYT AGL2011-22447]
- CSIC, Spain [201370E068]
- BACCHUS (FP7-KBBE-2012-6-single stage, European Commission Grant) [312090]
- MINECO
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.
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