Abstract
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.
Highlights
Prostate cancer (PCa) is the second most common cancer and the second leading cause of cancer-related death in men, with over 300,000 cases diagnosed annually in the United States [1] with an increasing incidence worldwide due to the growth and aging of the global population [2]
30 percent of men treated for PCa with surgery or radiation have evidence of recurrent disease, and in a subset of men, levels of prostate-specific antigen (PSA) continues to rise after treatment [3]
A phase II study examining the effects of pomegranate juice (PJ) in men with rising PSA following surgery or radiation for PCa demonstrated that consumption of 8 ounces of PJ significantly increased the PSA doubling time, from 15 to 54 months, suggesting an inhibitory action of PJ metabolites on PCa cell growth [6]
Summary
Prostate cancer (PCa) is the second most common cancer and the second leading cause of cancer-related death in men, with over 300,000 cases diagnosed annually in the United States [1] with an increasing incidence worldwide due to the growth and aging of the global population [2]. 30 percent of men treated for PCa with surgery or radiation have evidence of recurrent disease, and in a subset of men, levels of prostate-specific antigen (PSA) continues to rise after treatment [3]. Under these circumstances, rising PSA represents tumor growth, and men with shorter doubling times of PSA value are presumed to have more rapidly growing tumors [4, 5].
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