ellagitannin and Prostatic-Neoplasms

Ellagitannins is a kind of phenolic compounds with many biological activities. Recent studies have found that the effective ingredients of these compounds have close relationship with their colon-derived bacteria metabolites, that is urolithins. The objective of this study was to review the structure characteristics, types and distribution of urolithins, improvement in diseases related to prostate, breast and colon, as well as anti-cancer, anti-oxidation, anti-inflammation and other biological activities. The present review will lay the foundation for development and utilization of urolithins.

Topics: Breast Neoplasms; Colonic Neoplasms; Coumarins; Female; Humans; Hydrolyzable Tannins; Inflammation; Intestines; Male; Prostatic Neoplasms

Black raspberry (BRB) phytochemicals demonstrate anti-carcinogenic properties in experimental models, including prostate cancer. Two BRB foods, a confection and nectar, providing a consistent and reproducible product for human clinical studies are designed and characterized.. Men with clinically localized prostate cancer are sequentially enrolled to a control group or one of four intervention groups (confection or nectar, 10 or 20 g dose; n = 8 per group) for 4 weeks prior to prostatectomy. Primary outcomes include: safety, adherence, and ellagitannin metabolism. Adherence to the intervention is >96%. No significant (≥grade II) toxicities are detected. Urinary urolithins (A, B, C, and D) and dimethyl ellagic acid (DMEA) quantified by Ultra high performance liquid chromatography tandem mass spectroscopy (UPLC/MS/MS) indicate a dose-dependent excretion yet heterogeneous patterns among men. Men in the BRB confection groups have greater urinary excretion of the microbial urinary metabolites urolithin A and DMEA, suggesting that this food matrix provides greater colonic microflora exposure.. Fully characterized BRB confections and nectar are ideal for food-based large phase III human clinical studies. BRB products provide a bioavailable source of BRB phytochemicals, however large inter individual variation in polyphenol metabolism suggests that host genetics, microflora, and other factors are critical to understanding bioactivity and metabolism.

Topics: Aged; Biomarkers; Dose-Response Relationship, Drug; Humans; Hydrolyzable Tannins; Male; Middle Aged; Prostatic Neoplasms; Rubus

Plant polyphenols are widespread in the American diet, yet estimated intake is uncertain. We examine the application of the Polyphenol Explorer® (PED) database to quantify polyphenol and ellagitannin (ET) intake of men with prostate cancer and tested the implementation of diets restricted in polyphenols or ETs.. Twenty-four men enrolled in a 4-week trial were randomized to usual, low-polyphenol or low-ET diet. Estimated polyphenol and ET intakes were calculated from 3-day diet records utilizing the PED. Urine and plasma metabolites were quantified by UPLC-MS. Adherence to the restricted diets was 95% for the low polyphenol and 98% for low-ET diet. In the usual diet, estimated dietary polyphenol intake was 1568 ± 939 mg/day, with coffee/tea beverages (1112 ± 1028 mg/day) being the largest contributors and estimated dietary ET intake was 12 ± 13 mg/day. The low-polyphenol and low-ET groups resulted in a reduction of total polyphenols by 45% and 85%, respectively, and omission of dietary ETs. UPLC analysis of urinary host and microbial metabolites reflect ET intake.. PED is a useful database for assessing exposure to polyphenols. Diets restricted in total polyphenol or ET intake are feasible and UPLC assessment of ET metabolites is reflective of dietary intake.

Topics: Aged; Databases, Factual; Diet; Humans; Hydrolyzable Tannins; Male; Middle Aged; Polyphenols; Prostatic Neoplasms

Activity-guided isolation of 80% acetone extract of Cornus alba, which is traditionally used as an anti-inflammatory, hemostatic and diuretic in Korea, yielded one novel compound, tentatively designated cornusiin H (13), together with 12 known compounds. The known compounds included four flavonoids (catechin (1), quercetin-3-O-β-D-glucuronide (2), quercetin-3-O-β-D-glucopyranoside (3), kaempferol-3-O-β-D-glucopyranoside (4)) and eight hydrolysable tannins (gallic acid (5), 2,6-di-O-galloyl-hamamelofuranoside (6), 2-galloyl-4-caffeoyl-L-threonic acid (7) 2,3-di-O-galloyl-4-caffeoyl-L-threonic acid (8), 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranoside (9), cornusiin B (10), cornusiin A (11) and camptothin B (12)). All compounds exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH)-free radical scavenging activity. Especially, the radical scavenging activities of 6 and 9-13 were higher than that of vitamin C. Compounds 9, 11, 12 and 13 inhibited the production of nitric oxide (NO) in lipopolysaccharide-stimulated RAW264.7 cells to the same degree as N(G)-Monomethyl-L-arginine (L-NMMA). When the antiproliferative effects of the isolated compounds were assessed in prostate cancer cells, the dimeric ellagitannins (11-13) selectively inhibited LNCaP hormone-dependent prostate cancer cells. Flow cytometry analysis indicated that the dimeric ellagitannins induced apoptosis and S-phase arrest. These results suggest that dimeric ellagitannins from Cornus alba can be developed as functional materials or herbal medicines for prostate tumors such as benign prostate hyperplasia and early-stage prostate cancer.

Topics: Animals; Antioxidants; Apoptosis; Cell Line, Tumor; Cornus; Cytostatic Agents; Humans; Hydrolyzable Tannins; Macrophages; Male; Mice; Molecular Structure; Nitric Oxide; Prostatic Neoplasms; RAW 264.7 Cells; S Phase Cell Cycle Checkpoints

The Eph-ephrin system comprises emerging proteins involved in many pathophysiological processes. The pharmacological activity of the main metabolites derived from the intake of some classes of (poly)phenolic compounds, such as caffeoylquinic acids, flavan-3-ols, and ellagitannins, on the Eph-ephrin interaction was evaluated at physiological concentrations. Functional studies to elucidate their role in prostate cancer were also performed.. Among the 21 phenolics screened by an ELISA-binding assay, just urolithin C, urolithin D, and ellagic acid succeeded to inhibit the EphA2-ephrin-A1 binding. Urolithin D, the most active, was a competitive and reversible antagonist of EphA receptors able to discriminate between EphA and EphB receptors, showing intra-classes selectivity. Molecular modeling and structure-activity relationships shed light on the binding mode and selective activity of urolithin D. This catabolite blocked EphA2 phosphorylation mediated by ephrin-A1, while lacking cytotoxicity and anti-proliferative effects, and was inactive on the EphA2 kinase assay.. The mechanisms behind the cancer preventive properties of foods rich in flavan-3-ols and caffeoylquinic acids are not associated with metabolic pathways directly linked to the Eph-ephrin system. However, the ellagitannin-derived colonic metabolite urolithin D was able to exert remarkable and selective EphA-ephrin-A inhibition, which might impact on prostate cancer prevention.

Topics: Anticarcinogenic Agents; Cell Line, Tumor; Cell Proliferation; Coumarins; Humans; Hydrolyzable Tannins; Male; Models, Molecular; Molecular Dynamics Simulation; Phosphorylation; Prostatic Neoplasms; Receptor, EphA2

The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10microg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R(-) cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Hydrolyzable Tannins; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; Lythraceae; Male; Plant Extracts; Prostatic Neoplasms; Protein Serine-Threonine Kinases; TOR Serine-Threonine Kinases

Angiogenesis is critical to tumor growth and is stimulated by tissue hypoxia due to poor oxygen delivery. In turn, cellular hypoxia leads to angiogenesis via the induction of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at a cellular level. Pomegranate juice and extracts, which are rich sources of ellagitannins, have been shown to have chemopreventive potential against prostate cancer, but there have been no studies on the effects of an ellagitannin-rich pomegranate extract on angiogenesis. Human prostate cancer cells (LNCaP) and human umbilical vein endothelial cells (HUVEC) were incubated with a pomegranate extract standardized to ellagitannin content (POMx), under normoxic and hypoxic conditions in vitro. Human prostate cancer cells (LAPC4) were injected subcutaneously into severe combined immunodeficient (SCID) mice and the effects of oral administration of POMx on tumor growth, microvessel density, and HIF-1alpha and VEGF expression were determined after 4 weeks of treatment. POMx inhibited the proliferation of LNCaP and HUVEC cells significantly under both normoxic and hypoxic conditions. HIF-1alpha and VEGF protein levels were also reduced by POMx under hypoxic conditions. POMx decreased prostate cancer xenograft size, tumor vessel density, VEGF peptide levels and HIF-1alpha expression after 4 weeks of treatment in SCID mice. These results demonstrate that an ellagitannin-rich pomegranate extract can inhibit tumor-associated angiogenesis as one of several potential mechanisms for slowing the growth of prostate cancer in chemopreventive applications. Further studies in humans are needed to confirm that angiogenesis can be inhibited by an ellagitannin-rich pomegranate extract administered orally as a dietary supplement.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Hydrolyzable Tannins; Hypoxia; In Vitro Techniques; Lythraceae; Male; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Plant Extracts; Prostatic Neoplasms