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

Authors and Affiliations:

Joana Liberal^1,2, Anália Carmo^2,3, Célia Gomes^4,5, Maria Teresa Cruz^2,6, Maria Teresa Batista^2,6

¹ Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco,

6000-767 Castelo Branco, Portugal

² CNC.IBILI, Universidade de Coimbra, 3004-504 Coimbra, Portugal

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

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

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

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

Abstract:

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.

Journal: Investigational New Drugs

Link: https://link.springer.com/article/10.1007%2Fs10637-017-0483-7