Comparison of anti-proliferative effects of urolithins, ellagitannin gut metabolites, and non-steriodal antiandrogens on androgen-dependant prostate cancer cell line LNCaP

Urolithins, hydroxylated derivatives of 6 H-dibenzo[b;d]pyran-6-one, are products of colonic microflora metabolism of ellagitannins. Their presence in blood and faeces was detected after ingestion of ellagitannin rich products such as pomegranate and walnuts by humans and isolated ellagitannins and acorns in animal studies. Moreover urolitins are more bioavailable than their mother compounds and may contribute to systemic effects observed after ellagitannin ingestion [1]. In this study, we examined the effects of the urolithin A, B and C (concentration 10 – 40 mM; 72h) on androgen-dependant cancer cell line LNCaP proliferation and compared them with the action of non-steroidal antiandrogen, flutamide, and it's main active metabolite 2-hydroxyflutamide. Proliferation was determined by DNA-Hoechst 33258 stain complexes fluorescence intensity measurement in cell lysates. Cells were also double stained with Annexin V-FITC/propidium iodide and tested for apoptosis by flow cytometry. All tested urolithins dose-dependently inhibited the proliferation of LNCaP cells. The urolithin A exhibited the most potent anti-proliferative activity, comparable to that of 2-hydroxyflutamide, reaching 40, 60 and 70 percent of growth inhibition for concentrations of 10mM, 20mM and 40mM, respectively. We also examined combined actions of synthetic antiandrogens and urolithins. Addition of urolithin A caused statistically significant (p < 0.05) reduction of LNCaP cells proliferation in comparison to antiandrogens alone. Apoptosis was dose-dependently induced in LNCaP cells by urolithin A. These results may add rationale to use ellagitannin rich products and plant extracts in prostate cancer chemoprevention.

Acknowledgements: This study was supported by research grant 2011/01/D/NZ4/01261 from polish National Science Center.

Keywords: urolithin, prostate cancer, LNCaP, ellagitannin

References:

[1] Espin JC, Larrosa M et al. 2013. Evid Based Complement Alternat Med; Article Number 270418