Pomegranate juice, in the last several years, has gained tremendous attention for its proven ability to slow down prostate cancer as evident by reduced prostate-specific antigen doubling time. However, a bioactive compound responsible for this action has not yet been confirmed and thus, limited its chemo-preventive/therapeutic potential. Pharmacokinetic studies of oral consumption of pomegranate juice in human have shown partial hydrolysis of ellagitannins, major component in the juice, into ellagic acid which is subsequently converted to various urolithin metabolites by the gut microbial digestion. Urolithins are shown to have extended plasma half-life and are detected in urine up to 48 after oral consumption of pomegranate juice. We investigated the potential of ellagic acid and major urolithin metabolites; urolithin A and urolithin B, that were synthesized in our laboratory, in inhibiting the growth and survival of androgen-independent prostate cancer cells, PC-3 and DU-145 cells in vitro. We found significantly high dose and time-dependent inhibition of growth and proliferation of both cell lines by all three compounds tested. Ellagic acid was found to be the most potent inhibitor as evident by significantly lower IC50 of 8.17 µM and 1.57µM respectively for DU-145 and PC-3 cells after 48 hours. Urolithin B was more efficient than Urolithin A against DU-145 cells (IC50 of 17.42µM vs. 73.78µM) while it was reversed in PC-3 cells (IC50 of 92.25 µM vs. 36.96 µM). Similarly, these compounds also induced substantial levels of dose-dependent apoptosis in either cell lines, however, with variable sensitivity. Western blot analysis of signaling proteins to elucidate the molecular mechanisms of observed effects correlated with altered levels of proteins that mediate cell-cycle regulation. P21, an inhibitor of CDK2-CyclinA/E complex that regulates protein elongation and cell-cycle progression from G1 to S phase was highly upregulated in compound-treated PC-3 cells and DU-145 cells, while cyclinD1 which regulates G1 to S phase transition in consort with CDK4 was significantly decreased in treated cells in comparison to untreated and vehicle-treated control. Studies are underway to understand the synergistic effects between these compounds, in vitro and in vivo. Taken together, our results indicates EA and its gut metabolites are significant anti-survival and anti-proliferation candidates against prostate cancer cells and hold a tremendous chemo-therapeutic and chemo-preventive potential, for its high efficacy and natural, low toxic source.

Citation Format: Anil Poudel, Manicka V. Vadhanam, Joseph Burlison. Efficacy of ellagic acid and its major urolithin metabolites in inhibiting growth of prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2014-4108