Pomegranate Ellagitannin-Derived Metabolites Inhibit Prostate Cancer Growth and Localize to the Mouse Prostate Gland

Abstract

Our group has shown in a phase II clinical trial that pomegranate juice (PJ) increases prostate specific antigen (PSA) doubling time in prostate cancer (CaP) patients with a rising PSA. Ellagitannins (ETs) are the most abundant polyphenols present in PJ and contribute greatly towards its reported biological properties. On consumption, ETs hydrolyze to release ellagic acid (EA), which is then converted by gut microflora to 3,8-dihydroxy-6H-dibenzo [b,d]pyran-6-one (urolithin A, UA) derivatives. Despite the accumulating knowledge of ET metabolism in animals and humans, there is no available data on the pharmacokinetics and tissue disposition of urolithins. Using a standardized ET-enriched pomegranate extract (PE), we sought to further define the metabolism and tissue distribution of ET metabolites. PE and UA (synthesized in our laboratory) were administered to C57BL/6 wild-type male mice, and metabolite levels in plasma and tissues were determined over 24 h. ET metabolites were concentrated at higher levels in mouse prostate, colon, and intestinal tissues as compared to other tissues after administration of PE or UA. We also evaluated the effects of PE on CaP growth in severe combined immunodeficient (SCID) mice injected subcutaneously with human CaP cells (LAPC-4). PE significantly inhibited LAPC-4 xenograft growth in SCID mice as compared to vehicle control. Finally, EA and several synthesized urolithins were shown to inhibit the growth of human CaP cells in vitro. The chemopreventive potential of pomegranate ETs and localization of their bioactive metabolites in mouse prostate tissue suggest that pomegranate may play a role in CaP treatment and chemoprevention. This warrants future human tissue bioavailability studies and further clinical studies in men with CaP.

Dietary agents for chemoprevention of prostate cancer

“…Furthermore, oral administration of pomegranate fruit extract to athymic nude mice implanted with androgen-sensitive CWR22Rν1 cells resulted in significant inhibition in tumor growth concomitant with a decrease in serum PSA levels [31]. This data was corroborated by a recent report where significant inhibition of LAPC-4 CaP xenograft growth was observed by Seeram et al, in the SCID mouse model [32].…”

Roles of Plant Extracts and Constituents in Cervical Cancer Therapy

“…It was reported in this investigation that the all these fruit extracts except lingonberry, exhibited antiproliferative activity due to their high content of ellagitannins. Ellagitannins and ellagitannin-rich fruit extracts have also been reported earlier to inhibit cancer cell growth in other studies, possibly due to release of the potent antiproliferative compound, ellagic acid under physiological conditions (Castonguay et al, 1997;Losso et al, 2004;Larrosa et al, 2006;Misikangas et al, 2007;Ross et al, 2007;Seeram et al, 2007). On the other hand, the tannin-rich extract of lingonberry, which consisted almost entirely of proanthocyanidins, was reported to be the constituents largely responsible for the antiproliferative effects (McDougall et al, 2008).…”

“…Among the studies reviewed here, there are few which have indicated antitumor activity in vivo such as topotecan (Yakushiji et al, 1997), mixture of flavonoids complexes in milk thistle (Post-White et al, 2007) and ellagic acid (Misikangas et al, 2007;Seeram et al, 2007). Raddeanin A, a triterpenoid saponin from Anemone raddeana has also demonstrated good antitumor activity.…”

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

“…Our recent study [31] showed that EA was detected in serum (134 ng/ml) and prostate (676 ng/ml) after intraperitoneal administration of pomegranate extract in mouse. It is a significant observation that EA is more targeted to prostate tissue which implies the beneficial role of pomegranate against prostate cancer.…”

“…Our group has demonstrated that 8 ounces of pomegranate juice consumed daily following primary treatment of prostate cancer significantly prolonged prostate specific antigen (PSA) doubling time from 15 months to 54 months [30]. We have also shown that pomegranate ellagitannins suppress prostate tumor formation in a SCID mouse xenograft model [31].…”