coumestrol and Prostatic-Neoplasms

Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25-2.92)], genistein [1.51 (1.02-2.22), daidzein [1.80 (1.18-2.75) and glycitein [1.67 (1.15-2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93-2.25), 1.65 (1.07-2.54), 1.73 (1.13-2.66) and 1.80 (1.18-2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.

Topics: Coumestrol; Humans; Isoflavones; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Risk; United States

Coumestrol is the one of the major phytoestrogens which is abundant in soybeans, legumes, brussel sprouts, and spinach. The beneficial effects of coumestrol are well known in various biological processes including; neuroprotective effects on the nervous system, function of the female reproductive system, anti-bacterial properties, and anti-cancer effects. Although the anti-tumor activity of coumestrol has been demonstrated for ovarian, breast, lung, and cervical cancers, little is known of its effects on prostate cancer. Therefore, in the present study, we investigated the chemotherapeutic effects of coumestrol on two prostate cancer cell lines, PC3 and LNCaP. Our results showed that coumestrol decreased proliferation and migration and induced apoptosis in both PC3 and LNCaP cells. Moreover, effects of coumestrol on cell signaling pathways were investigated and it increased phosphorylation of ERK1/2, JNK, P90RSK, and P53 proteins in a dose- and time-dependent manner whereas phosphorylation of AKT was reduced by coumestrol under the same conditions for culture of PC3 and LNCaP cells. In addition, mitochondrial dysfunction was induced by coumestrol as evidenced by a significant loss of mitochondrial membrane potential. Furthermore, cleavage of caspase-3 and caspase-9, the apoptotic proteins associated with mitochondria, also changed in response to coumestrol. Coumestrol also caused mitochondrial dysfunction resulting in an increase in ROS production in PC3 and LNCaP cells. These results suggest that coumestrol can inhibit progression of prostate cancer and may be a novel chemotherapeutic agent for treatment of prostate cancer via effects mediated via the PI3K/AKT and ERK1/2 and JNK MAPK cell signaling pathways. J. Cell. Physiol. 232: 862-871, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Coumestrol; Extracellular Signal-Regulated MAP Kinases; Humans; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Models, Biological; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species

The 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5) is involved in estrogen and androgen metabolism. In our study we tested the influence of environmental hormones, such as phytoestrogens (flavonoids, coumarins, coumestans), on reductive and oxidative 17beta-HSD activity of the human 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5). These dietary substances were shown to be potent inhibitors of aromatase, different 17beta-HSDs and seem to play an important role in delay of development of hormone dependent cancers. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many dietary compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among the group of flavones inhibitor potency is growing with increasing number of hydroxylations. We suggest that these substances are bound to the hydrophilic cofactor-binding pocket of the enzyme. An interesting inhibition pattern is observed for 18beta-glycyrrhetinic acid, which has no influence on the oxidative but only on the reductive reaction. This indicates that this substrate binds to pH- and cofactor-depending sites at the active center of the enzyme.

Topics: 17-Hydroxysteroid Dehydrogenases; Aromatase Inhibitors; Binding Sites; Breast Neoplasms; Coumestrol; Diet; Enzyme Inhibitors; Estrogens; Estrogens, Non-Steroidal; Female; Gene Expression; Genistein; Glycine max; Glycyrrhetinic Acid; Humans; Hydrogen-Ion Concentration; Hydroxylation; Isoenzymes; Isoflavones; Male; Models, Molecular; Oxidation-Reduction; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Quercetin; Recombinant Proteins; Testosterone; Zearalenone

Prostate cancer is one of the most common male cancers in Western countries, yet the incidence of this fatal disease remains low in Asian populations. Environmental factors such as diet play an important role in hormone-dependent cancer etiology, and a high phytoestrogen intake may be one factor contributing to the low prostate cancer mortality in Eastern populations. In this study, we investigated the effects of the phytoestrogens genistein, daidzein, coumestrol, and equol on cell growth and DNA damage (strand breakage) in two human prostate tumor cell lines: androgen receptor-positive LNCaP and androgen receptor-negative PC-3. Each compound caused growth inhibition at physiologically relevant concentrations (<10 microM). Genistein induced DNA damage in both cell lines at <10 microM. Daidzein inhibited cell growth at 10-100 microM yet had no effect on DNA damage at up to 500 microM. Thus, despite their structural similarities, different phytoestrogens inhibit prostate tumor cell growth by independent mechanisms.

Topics: Antineoplastic Agents, Phytogenic; Cell Division; Cell Transformation, Neoplastic; Chromans; Coumestrol; DNA Damage; Equol; Estrogens, Non-Steroidal; Genistein; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

Histochemical analyses estrogen (ER) and progesterone (PgR) receptors in breast cancer were statistically correlated with results of dextran-coated charcoal (DDC) and sucrose gradient assays. Correlated for ER was 91% of 363 cases, and for PgR 88% of 255 specimens. Breast cancer ER/PgR positivity by histochemistry correlated with a favorable clinical response to endocrine therapies in 72% of 25 cases, while ER/PgR negativity correlated with a lack of response in 96% of 22 cases with Stage IV disease. Nuclear ER/PgR correlated with a poor response to therapy in 8 of 12 patients. An in vitro technique to detect nuclear translocation of ER revealed two groups of ER positive cases, with 11 of 17 exhibiting translocation and 6 not displaying translocation. In prostatic carcinoma, 72% of 65 men were positive for ER and/or androgen receptor. Comparison of specimens obtained without and with electrocautery revealed a preponderance of nuclear binding in the latter, suggesting heat-induced nuclear translocation of receptor. coumestrol, a naturally fluorescent, entirely unaltered estrogen was also used for histochemical detection of ER. Results correlated with ER by DCC in 87% of 61 breast cancers. Coumestrol was additionally used to visually observe receptor and nuclear translocation of ER in intact whole cells in culture.

Topics: Breast Neoplasms; Carcinoma; Coumestrol; Estrogens; Female; Histocytochemistry; Humans; Male; Progesterone; Prostatic Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid