Investigational New Drugs

, Volume 35, Issue 6, pp 671–681 | Cite as

Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells

  • Joana LiberalEmail author
  • Anália Carmo
  • Célia Gomes
  • Maria Teresa Cruz
  • Maria Teresa Batista


Ellagitannins have been gaining attention as potential anticancer molecules. However, the low bioavailability of ellagitannins and their extensive metabolization in the gastrointestinal tract into ellagic acid and urolithins suggest that the health benefits of consuming ellagitannins rely on the direct effects of their metabolites. Recently, chemopreventive and chemotherapeutic activities were ascribed to urolithins. Nonetheless, there is still a need to screen and evaluate the selectivity of these molecules and to elucidate their cellular mechanisms of action. Therefore, this work focused on the antiproliferative effects of urolithins A, B and C and ellagic acid on different human tumor cell lines. The evaluation of cell viability and the determination of the half-maximal inhibitory concentrations indicated that the sensitivity to the studied urolithins varied markedly between the different cell lines, with the bladder cancer cells (UMUC3) being the most susceptible. In UMUC3 cells, urolithin A was the most active molecule, promoting cell cycle arrest at the G2/M checkpoint, increasing apoptotic cell death and inhibiting PI3K/Akt and MAPK signaling. Overall, the present study emphasizes the chemopreventive/chemotherapeutic potential of urolithins, highlighting the stronger effects of urolithin A and its potential to target transitional bladder cancer cells.


Apoptosis Cell cycle Ellagitannins Intracellular signaling pathways UMUC3 Urolithins 



We acknowledge Professor Conceição Pedroso Lima and Doctor Eugénia Carvalho (Center for Neurosciences and Cell Biology, University of Coimbra) for kindly supplying the HepG2 and BJ cell lines, respectively. We also thank the assistance of the CNC Flow Cytometry Core Facility, where the flow cytometry experiments were performed.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


The study was supported by the European Regional Development Fund (ERDF) through the Centro 2020 Regional Operational Programme: (project CENTRO-01-0145-FEDER-000012-HealthyAging2020), the COMPETE 2020 Operational Programme for Competitiveness and Internationalisation, the Portuguese national funds via the FCT (Fundação para a Ciência e a Tecnologia, I.P.; project POCI-01-0145-FEDER-007440) and a Ph.D. fellowship (SFRH/BD/72918/2010).

Ethical approval

This article does not contain any data from studies involving human participants or animals.


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Escola Superior de Saúde Dr. Lopes DiasInstituto Politécnico de Castelo BrancoCastelo BrancoPortugal
  2. 2.CNC.IBILIUniversity of CoimbraCoimbraPortugal
  3. 3.Serviço de Patologia ClinicaCentro Hospitalar e Universitário de CoimbraCoimbraPortugal
  4. 4.Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  5. 5.Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  6. 6.Faculty of PharmacyUniversity of CoimbraCoimbraPortugal

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