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

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Summary

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco, Campus da Talagueira, Avenida do Empresário, 6000-767, Castelo Branco, Portugal

    Joana Liberal

  2. CNC.IBILI, University of Coimbra, 3004-504, Coimbra, Portugal

    Joana Liberal, Anália Carmo, Maria Teresa Cruz & Maria Teresa Batista

  3. Serviço de Patologia Clinica, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal

    Anália Carmo

  4. Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal

    Célia Gomes

  5. Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal

    Célia Gomes

  6. Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal

    Maria Teresa Cruz & Maria Teresa Batista

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  1. Joana Liberal
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  2. Anália Carmo
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Correspondence to Joana Liberal.

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The authors declare that they have no conflict of interest.

Funding

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).

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Liberal, J., Carmo, A., Gomes, C. et al. Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells. Invest New Drugs 35, 671–681 (2017). https://doi.org/10.1007/s10637-017-0483-7

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  • DOI: https://doi.org/10.1007/s10637-017-0483-7

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