Essential Elements and Isoflavonoids in the Prevention of Prostate Cancer.

The intake of selected minerals, especially zinc, calcium and selenium, and high consumption of dietary isoflavones are recognised as factors influencing prostate cancer risk. Moreover, changes in levels of some essential elements are characteristic of the disease. Here, we examined the combined effects of main dietary isoflavonoids (genistein, daidzein and its metabolite, equol) and minerals implicated in prostate cancer, namely zinc, selenium, copper, iron and calcium, on LNCaP prostate cancer cells proliferation. Secondly, we evaluated the influence of the combinations on genotoxicity of model mutagens, 4-nitroquinoline oxide (4NQO) and 2-aminoanthracene (2AA), in the umu test. All combinations of isoflavonoids and minerals inhibited prostate cancer cells growth. However, only mixtures with iron ions had significantly stronger effect than the phytochemicals. Interestingly, we observed that only genistein attenuated genotoxicity of 4NQO. The addition of any tested mineral abolished this effect. All tested isoflavonoids had anti-genotoxic activity against 2AA, which was significantly enhanced in the presence of copper sulphate. Our results indicate that the tested minerals in physiological concentrations had minimal influence on the anti-proliferative activity of isoflavonoids. However, they significantly modulated the anti-genotoxic effects of isoflavonoids against both metabolically activated and direct mutagens. Thus, the minerals intake and nutritional status may modulate protective action of isoflavonoids.

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

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.

The effects of urolithins on the response of prostate cancer cells to non-steroidal antiandrogen bicalutamide.

BACKGROUND: Urolithins are bioavailable products of gut microbiota metabolism of ellagitannins. Their biological activity includes anti-cancer effects. PURPOSE: The aim of this study was to explore the effects of urolithins on prostate cancer cells and activity of clinically used anti-androgen, bicalutamide. METHODS: Prostate cancer cells were treated with urolithin A, urolithin B, urolithin C or their combinations with bicalutamide. Cell proliferation was determined by DNA fluorescence with Hoechst 33258. The combination index method was used to examine interactions. Apoptosis and androgen receptor (AR) localization were analysed by flow cytometry. Prostate specific antigen (PSA) secretion was measured by ELISA. RESULTS: Urolithins inhibited proliferation of LNCaP prostate cancer cells. The mixtures of bicalutamide with uroA and uroB had additive anti-proliferative effect. All tested urolithins induced apoptosis of LNCaP cells. However, the combinations of bicalutamide with urolithin A and urolithin B had attenuated pro-apoptotic activity. UroA and uroC decreased DHT-induced PSA secretion. In contrast, uroB impaired PSA lowering effect of bicalutamide. UroA, individually and in combination with bicalutamide, promoted cytoplasmic localization of AR. CONCLUSION: Urolithins might contribute to chemopreventive activity of ellagitannin rich preparations. Our results support use of ellagitannin rich preparations in prostate cancer chemoprevention, but advise caution in their potential use in complementary therapy of prostate cancer. The differences in activity profiles of urolithins indicate that possible health benefits and interactions will depend on the type of produced ellagitannins metabolite.