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Planta Med 2019; 85(02): 118-125
DOI: 10.1055/a-0755-7715
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

The Activity of Urolithin A and M4 Valerolactone, Colonic Microbiota Metabolites of Polyphenols, in a Prostate Cancer In Vitro Model

Iwona J. Stanisławska
1   Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
3   Department of Bromatology, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
,
Sebastian Granica
1   Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
,
Jakub P. Piwowarski
1   Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
,
Joanna Szawkało
2   Faculty of Chemistry, University of Warsaw, Warsaw, Poland
,
Krzysztof Wiązecki
2   Faculty of Chemistry, University of Warsaw, Warsaw, Poland
,
Zbigniew Czarnocki
2   Faculty of Chemistry, University of Warsaw, Warsaw, Poland
,
Anna K. Kiss
1   Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
› Author Affiliations
Further Information

Publication History

received 25 May 2018
revised 24 September 2018

accepted 03 October 2018

Publication Date:
19 October 2018 (online)

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Abstract

The gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A (uroA) and 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone (M4), respectively, are among the main compounds absorbed into human system after ingestion of these polyphenols. The aim of this study was to establish the effects of M4, uroA, and their combinations on LNCaP cells, an androgen dependent prostate cancer in vitro model.. The LNCaP cells were incubated with increasing concentrations of tested metabolites. The cell proliferation was determined by measurement of DNA-bisbenzimide H 33 258 complexes fluorescence. The isobolographic analysis was used to establish the type of interaction between metabolites. The apoptosis, androgen receptor (AR) localization, and phosphorylation of Akt kinase were measured by flow cytometry. Prostate-specific antigen (PSA) secretion was determined by ELISA. M4 showed modest antiproliferative activity in LNCaP cells (IC50 = 117 µM; CI: 81 – 154). UroA decreased proliferation (IC50 = 32.7 µM; CI: 24.3 – 41.1) and induced apoptosis of LNCaP cells. The mixture of M4 with uroA had synergistic antiproliferative effect. Moreover, M4 potentiated inhibition of PSA secretion and enhanced retention of AR in cytoplasm caused by uroA. Interestingly, uroA increased levels of pSer473 Akt in LNCaP cells. These results show that colonic metabolites may contribute to chemoprevention of prostate cancer by varied polyphenol-rich diet or composite polyphenol preparations.

Key words

urolithin A - 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone - metabolization - microbiome - green tea - prostate cancer

Supporting Information

    The comparison of antiproliferative activity of M4 and EGCG, the parameters of the dose-effect curves of tested metabolites, EGCG and bic, the representative histograms of the changes of AR distribution in LNCaP cells, and the description of the synthesis of M4 are available as Supporting Information.

  • Supporting Information
 

  • References

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