Ellagitannins (ETs) from pomegranate juice (PJ) are bioactive
polyphenols with chemopreventive potential against
prostate cancer (PCa). ETs are not absorbed intact but are partially hydrolyzed in the gut to
ellagic acid (EA). Colonic microflora can convert EA to
urolithin A (UA), and EA and UA enter the circulation after PJ consumption. Here, we studied the effects of EA and UA on cell proliferation, cell cycle, and apoptosis in DU-145 and PC-3
androgen-independent PCa cells and whether combinations of EA and UA affected cell proliferation. EA demonstrated greater dose-dependent antiproliferative effects in both cell lines compared to UA. EA induced cell cycle arrest in S phase associated with decreased
cyclin B1 and
cyclin D1 levels. UA induced a G2/M arrest and increased
cyclin B1 and cdc2 phosphorylation at tyrosine-15, suggesting inactivation of the
cyclin B1/cdc2
kinase complex. EA induced apoptosis in both cell lines, while UA had a less pronounced proapoptotic effect only in DU-145. Cotreatment with low concentrations of EA and UA dramatically decreased cell proliferation, exhibiting synergism in PC-3 cells evaluated by isobolographic analysis and combination index. These data provide information on pomegranate metabolites for the prevention of PCa recurrence, supporting the role of gut flora-derived metabolites for
cancer prevention.