Urolithin A and Ellagic Acid Inhibit Prostate Cancer Through Different Molecular Mechanisms: Implications of Gut Microbiome Metabolism for Cancer Prevention

Abstract

There is an increased interest in the production by the gut microbiome of metabolites of phytochemicals with chemorpreventive activities. More information is needed on the mechanisms of action of these metabolites by comparison to the parent compounds from which they are derived. Following consumption of pomegranate juice, ellagitannins are hydrolyzed in the intestine leading to an increase in ellagic acid (EA) levels in the blood over a 5 hour period. Through the action of the microbiome, ellagic acid is converted into urolithins, which are then excreted in glucuronidated form in the urine between 12 and 56 hours after ingestion of a single glass of pomegranate juice containing 240 mg of ellagitannins. In order to examine the mechanisms whereby urolithin A (UA) inhibits cancer cell growth by comparison to ellagic acid (EA), DU-145 and PC-3 cancer cells were exposed to EA (15 to 60 μmol/L) or urolithin A (UA) (15 to 90 μmol/L) in vitro for 24 to 120 hours. Cell number, viability, activation of NF-kB, and cell cycle progression by FACS analysis were investigated. While both EA and UA inhibited cell proliferation, EA was more effective than UA in interfering with TNF alpha-induced NF-kB activation, while UA was more effective in inducing cell cycle arrest in G2/M phase by inducing phosphorylation of cdc2 and accumulation of cyclin B1 leading to cell death. Our findings demonstrate that urolithin A formed from ellagic acid by the gut microbiome could enhance the activity of ellagic acid through effects on different molecular targets.