European Journal of Nutrition

, Volume 56, Issue 2, pp 831–841

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

  • Antonio González-Sarrías
  • María Ángeles Núñez-Sánchez
  • Rocío García-Villalba
  • Francisco A. Tomás-Barberán
  • Juan Carlos Espín
Original Contribution

DOI: 10.1007/s00394-015-1131-7

Cite this article as:
González-Sarrías, A., Núñez-Sánchez, M.Á., García-Villalba, R. et al. Eur J Nutr (2017) 56: 831. doi:10.1007/s00394-015-1131-7

Abstract

Purpose

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.

Keywords

Urolithins Isourolithin A Ellagic acid Cell cycle Apoptosis Colon cancer 

Abbreviations

ACN

Acetonitrile

ATCC

American type culture collection

CRC

Colorectal cancer

DMSO

Dimethyl sulfoxide

FBS

Fetal bovine serum

FITC

Fluorescein isothiocyanate

Glur

Glucuronide

HPLC

High-performance liquid chromatography

IC50

Half-maximal inhibitory concentration

IsoUro

Isourolithin

MEM

Minimal essential medium

MeOH

Methanol

MS

Mass spectrometry

MTT

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

OD

Optical density

PBS

Phosphate-buffered saline

PI

Propidium iodide

SD

Standard deviation

UGTs

UDP-glucuronosyltransferases

Uro

Urolithins

μM

Micromolar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Antonio González-Sarrías
    • 1
  • María Ángeles Núñez-Sánchez
    • 1
  • Rocío García-Villalba
    • 1
  • Francisco A. Tomás-Barberán
    • 1
  • Juan Carlos Espín
    • 1
  1. 1.Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and TechnologyCEBAS-CSICMurciaSpain

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