phytoestrogens and Prostatic-Neoplasms

Phytoestrogens are plant secondary metabolite that is structurally and functionally similar to mammalian estrogens, which have been shown to have various health benefits in humans. Isoflavones, coumestans, and lignans are the three major bioactive classes of phytoestrogens. It has a complicated mechanism of action involving an interaction with the nuclear estrogen receptor isoforms ERα and ERβ, with estrogen agonist and estrogen antagonist effects. Depending on their concentration and bioavailability in various plant sources, phytoestrogens can act as estrogen agonist or antagonists. Menopausal vasomotor symptoms, breast cancer, cardiovascular disease, prostate cancer, menopausal symptoms, and osteoporosis/bone health have all been studied using phytoestrogens as an additional standard hormone supplemental remedy. The botanical sources, techniques of identification, classification, side effects, clinical implications, pharmacological and therapeutic effects of their proposed mode of action, safety issues, and future directions for phytoestrogens have all been highlighted in this review.

Topics: Animals; Breast Neoplasms; Estrogens; Humans; Isoflavones; Male; Mammals; Phytoestrogens; Prostatic Neoplasms; Receptors, Estrogen

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.

Topics: Apoptosis; Genistein; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms

Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically a Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment has been well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.

Topics: Anticarcinogenic Agents; Diet; Humans; Male; Phytoestrogens; Prostatic Neoplasms

The quest for dietary patterns and supplements efficient in down-regulating prostate-specific antigen (PSA) concentrations among men with prostate cancer (PCa) or increased PCa risk has been long. Several antioxidants, including lycopene, selenium, curcumin, coenzyme Q10, phytoestrogens (including isoflavones and flavonoids), green tea catechins, cernitin, vitamins (C, E, D) and multivitamins, medicinal mushrooms (

Topics: Adult; Aged; Antioxidants; Catechin; Diet; Dietary Supplements; Humans; Male; Middle Aged; Phytoestrogens; Phytotherapy; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; Vitamins

Phytoestrogens may influence prostate cancer development. This study aimed to examine the association between prediagnostic circulating concentrations of isoflavones (genistein, daidzein, equol) and lignans (enterolactone and enterodiol) and the risk of prostate cancer. Individual participant data were available from seven prospective studies (two studies from Japan with 241 cases and 503 controls and five studies from Europe with 2,828 cases and 5,593 controls). Because of the large difference in circulating isoflavone concentrations between Japan and Europe, analyses of the associations of isoflavone concentrations and prostate cancer risk were evaluated separately. Prostate cancer risk by study-specific fourths of circulating concentrations of each phytoestrogen was estimated using multivariable-adjusted conditional logistic regression. In men from Japan, those with high compared to low circulating equol concentrations had a lower risk of prostate cancer (multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence interval [CI] = 0.39-0.97), although there was no significant trend (OR per 75 percentile increase = 0.69, 95 CI = 0.46-1.05, p

Topics: Aged; Case-Control Studies; Equol; Europe; Genistein; Humans; Isoflavones; Japan; Lignans; Male; Middle Aged; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Risk Factors

This updated meta-analysis was performed to clarify the relationship between phytoestrogens and prostate cancer risk. Twenty one case-control and two cohort studies were finally selected for this meta-analysis, totaling 11,346 cases and 140,177 controls. Analytical results showed that daidzein (OR = 0.85; 95% CI: 0.75-0.96), genistein (OR = 0.87; 95% CI: 0.78-0.98), and glycitein (OR = 0.89; 95% CI: 0.81-0.98) were associated with a reduction of prostate cancer risk, but total isoflavones (OR = 0.93; 95% CI: 0.84-1.04), equol (OR = 0.86; 95% CI: 0.66-1.14), total lignans (OROgna.05; 95% CI: 0.54-2.04), secoisolariciresinol (OR = 1.02; 95% CI: 0.83-1.24), matairesinol (OR = 0.91; 95% CI: 0.75-1.11), enterolactone (OR = 0.94; 95% CI: 0.73-1.20), and coumestrol (OR = 0.89; 95% CI: 0.76-1.06) were not. Sensitivity and publication bias analyses demonstrated that the pooled estimates were stable and reliable. The results support the notion that some phytoestrogens may have a role in decreasing the risk of prostate cancer. Additional large and well-designed cohort studies are needed to confirm these relationships.

Topics: Case-Control Studies; Cohort Studies; Diet, Healthy; Evidence-Based Medicine; Genistein; Humans; Isoflavones; Male; Men's Health; Phytoestrogens; Prostatic Neoplasms; Risk

The purpose of this review is to discuss some critical issues of isoflavones protective against the development of prostate cancer (PCa).. Data cited in this review were obtained primarily from PubMed and Embase from 1975 to 2015.. Articles were selected with the search terms "isoflavone", "Phytoestrogen", "soy", "genistin", and "PCa ".. Isoflavones do not play an important role on prostate-specific antigen levels reduction in PCa patients or healthy men. The effect of isoflavones on sex hormone levels and PCa risk may be determined by equol converting bacteria in the intestine, specific polymorphic variation and concentrations of isoflavones. The intake of various types of phytoestrogens with lower concentrations in the daily diet may produce synergistic effects against PCa. Moreover, prostate tissue may concentrate isoflavones to potentially anti-carcinogenic levels. In addition, it is noteworthy that isoflavones may act as an agonist in PCa.. Isoflavones play a protective role against the development of PCa. However, careful consideration should be given when isoflavones are used in the prevention and treatment of PCa.

Topics: Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms

This study uses current epidemiological data to evaluate whether phytoestrogen intake is associated with a reduced risk of prostate cancer. We performed a random-effect meta-analysis of published data retrieved from PubMed, Web of Science, ProQuest, and CNKI, which was supplemented by a manual search of relevant references. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Subgroup analysis and meta-regression were performed to explore the source of heterogeneity. Sensitivity analysis was evaluated to assess the stability of the results. Egger's test and funnel plots were used to detect the existence of publication bias. We retrieved 507 papers, and 29 studies were ultimately confirmed as eligible. The meta-analysis showed that phytoestrogen intake was significantly associated with a reduced risk of prostate cancer, with an odds ratio (OR) of 0.77 (95% CI 0.66-0.88; I(2)  = 77.6%). The food/nutritional sources that were significantly associated with a reduced risk of prostate cancer included soy and soy products, tofu, legumes, daidzein, and genistein. Subgroup analysis indicated that the associations were significant among Asians and Caucasians, but not among Africans. Meta-regression revealed that the pooled OR increased with the number of cases in the studies. The results might be affected by publication bias based on the Eggers' test (p = 0.011) and the asymmetry of the funnel plot. Phytoestrogen intake may reduce the risk of prostate cancer in Asians and Caucasians. Regular intake of food that is rich in phytoestrogens, such as soy/soy products or legumes, should be recommended.

Topics: Humans; Incidence; Male; Phytoestrogens; Prostatic Neoplasms; Risk; Risk Reduction Behavior

With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial - there are non-modifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet-cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications.

Topics: Adult; Antioxidants; Diet; DNA Methylation; Epigenesis, Genetic; Genistein; Glycine max; Histone Code; Humans; Isoflavones; Male; MicroRNAs; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Factors

Epidemiologic studies have reported various results relating phytoestrogens to prostate cancer (PCa). The aim of this study was to provide a comprehensive meta-analysis on the extent of the possible association between phytoestrogens (including consumption and serum concentration) and the risk of PCa.. Eligible studies were retrieved via both computer searches and review of references. The summary relative risk ratio (RR) or odds ratio (OR) and 95% confidence interval (CI) were calculated with random effects models.. A total of 11 studies (2 cohort and 9 case-control studies) on phytoestrogen intake and 8 studies on serum concentration were included in the meta-analysis. The pooled odds ratio (OR) showed a significant influence of the highest phytoestrogens consumption (OR 0.80, 95% CI 0.70-0.91) and serum concentration (OR 0.83, 95% CI 0.70-0.99) on the risk of PCa. In stratified analysis, high genistein and daidzein intake and increased serum concentration of enterolactone were associated with a significant reduced risk of PCa. However, no significant associations were observed for isoflavone intake, lignans intake, or serum concentrations of genistein, daidzein, or equol.. The overall current literature suggests that phytoestrogen intake is associated with a decreased risk of PCa, especially genistein and daidzein intake. Increased serum concentration of enterolactone was also associated with a significant reduced risk of PCa. Further efforts should be made to clarify the underlying biological mechanisms.

Topics: Case-Control Studies; Humans; Male; Observational Studies as Topic; Phytoestrogens; Prostatic Neoplasms; Risk Factors

All the currently available cancer therapeutic options are expensive but none of them are safe. However, traditional plant-derived medicines or compounds are relatively safe. One widely known such compound is beta-sitosterol (BS), a plant derived nutrient with anticancer properties against breast cancer, prostate cancer, colon cancer, lung cancer, stomach cancer, ovarian cancer, and leukemia. Studies have shown that BS interfere with multiple cell signaling pathways, including cell cycle, apoptosis, proliferation, survival, invasion, angiogenesis, metastasis and inflammation. Most of the studies are incomplete partly due to the fact that BS is relatively less potent. But the fact that it is generally considered as nontoxic, the opposite of all currently available cancer chemo-therapeutics, is missed by almost all research communities. To offset the lower efficacy of BS, designing BS delivery for "cancer cell specific" therapy hold huge potential. Delivery of BS through liposome is one of such demonstrations that has shown to be highly promising. But further research did not progress neither in the field of drug delivery of BS nor in the field on how BS mediated anticancer activities could be improved, thus making BS an orphan nutraceutical. Therefore, extensive research with BS as potent anticancer nutraceutical is highly recommended.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Colonic Neoplasms; Dietary Supplements; Drug Delivery Systems; Female; Humans; Leukemia; Liposomes; Lung Neoplasms; Male; Neoplasms; Orphan Drug Production; Phytoestrogens; Prostatic Neoplasms; Signal Transduction; Sitosterols

Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.

Topics: Androgen Antagonists; Calcium, Dietary; Diabetes Mellitus, Type 2; Dietary Supplements; Fatty Acids; Humans; Male; Osteoporosis; Phytoestrogens; Prostatic Neoplasms; Selenium; Treatment Outcome; Vitamin D; Vitamin E

Diet is believed to play an important role in cancer. It has been revealed by epidemiological studies that Asian populations, who consume phytoestrogens in large amounts, have a lower incidence of prostate cancer in comparison with the Western world, where consumption of soy is lower. Genistein and daidzein, the soy phytoestrogens most widely studied, are believed to be potent anticancer agents and have been shown to possess anticancer properties. It has been shown that these compounds inhibit the growth of cancer cells through the modulation of genes controlling cell-cycle progression. Genistein inhibits the activation of the kappa light polypeptide gene enhancer in B-cells (NF-κB), signaling pathway, which is implicated in the balance between cell survival and programmed cell death (apoptosis). Antioxidant and antiangiogenesis properties of genistein have been also described. Soy isoflavones are also implicated in reversion of epigenetic events observed in prostate cancer. Significant advances have been made for understanding how soy isoflavones are implicated in protection against prostate cancer. However, more studies are needed to better-understand and elucidate all pathways mobilized by genistein and daidzein, in order to fully exploit their anticancer properties.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Epigenomics; Feeding Behavior; Genistein; Glycine max; Humans; Isoflavones; Male; NF-kappa B; Phytoestrogens; Prostatic Neoplasms

To review diet risk factors (RF) implied, more or less evidence-based, in the etiopathology of prostate carcinoma (PC), especially those that characterize the traditional Mediterranean diet (MD).. Literature review of PC related diet RF in MedLine, CancerLit, Science Citation Index y Embase. Search profiles were "Dietetic Factors/Nutritional Factors/Mediterranean Diet/Primary Prevention", and "Prostate Cancer".. Diet RF are associated with 35% of cancer mortality and 10-12% of PC mortality. The main diet RF, implied in the development of PC but with a protective effect, which are considered characteristic of MD are: high daily ingestion of vegetarian products (cereals, legumes, dried and fresh fruits, tubers, vegetables..); olive oil as main lipid source; low intake of animal saturated fat, processed red meat, milk and dairy products; regular consumption of small fish; and low alcohol intake (wine with meals). The MD contains many phytoactive compounds (lycopene, lupeol, quercetin, genistein, carnosol, resveratrol, catechins, vitamins..) with PC protective effects.. Diet RF have a role on prostatic carcinogenesis. Further epidemiologic studies with better designs are needed to clarify PC related diet RF. PC risk is reduced in persons on MD compared with those on Western diet. The preventive effect of MD is due to the great number and quality of phytochemicals with antioxidant and antinflammatory properties that contains.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Antioxidants; Carotenoids; Diet, Mediterranean; Dietary Fats; Dietary Fats, Unsaturated; Fishes; Flavonoids; Humans; Life Style; Male; Meat; Phytoestrogens; Polyphenols; Prostatic Neoplasms; Vegetables; Wine

An increasing amount of evidence points at important roles for estrogen receptors in prostate carcinogenesis and progression. Of the two estrogen receptors, estrogen receptor β is the most prominent within the prostate gland. Although there is much yet to be known, the findings from the discovery of the receptor in 1996 until now point at a role of the receptor in maintaining differentiation and reducing cellular proliferation in the prostate. Moreover, estrogen receptor β is the main target for phytoestrogens, perhaps at least partially explaining the difference in incidence of prostate cancer in the Western world compared to Asia where the intake of soy-based, phytoestrogen-rich food is higher. The tumor suppressive capability of estrogen receptor β makes it a promising drug target for the treatment and prevention of prostate cancer. This review will focus on different aspects of estrogen receptor signaling and prostate cancer.

Topics: Animals; Disease Progression; Estrogen Receptor beta; Humans; Male; Phytoestrogens; Prostate; Prostatic Neoplasms

Through the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has dramatically changed. Despite all efforts efficacy of a specific compound has not been proven, so far. In consequence, recommendations for a use of vitamins or other supplements with the intention of prostate cancer prevention should be avoided today. In contrast, there is some evidence that life style modification might be helpful: recent investigations suggest that smoking may be involved in prostate cancer carcinogenesis. In addition, there is evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet might not only prevent prostate cancer but also harbors additional beneficial effects on general health. This move from single compounds to more complex diets can be considered as a change of paradigm in prostate cancer prevention and could be the starting point of future epidemiological research. Disappointing findings with regards to nutritional cancer prevention contrast with a solid evidence concerning the efficacy of chemoprevention using 5a-reductase inhibitors: Long-term use of Finasteride and Dutasteride significantly reduces prostate cancer detection. Further candidate drugs are under investigation. However, translation of these findings into urological practice remains a matter of controversial discussion.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Dairy Products; Diet; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Male; Meat; Phytoestrogens; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Selective Estrogen Receptor Modulators; Selenium; Smoking Cessation; Vitamins

Many clinical studies have been carried out to determine the health benefits of soy protein and the isoflavones contained in soy. S-equol is not present in soybeans but is produced naturally in the gut of certain individuals, particularly Asians, by the bacterial biotransformation of daidzein, a soy isoflavone. In those intervention studies in which plasma S-equol levels were determined, a concentration of >5-10 ng/mL has been associated with a positive outcome for vasomotor symptoms, osteoporosis (as measured by an increase in bone mineral density), prostate cancer, and the cardiovascular risk biomarkers low-density lipoprotein cholesterol and C-reactive protein. These studies suggest that S-equol may provide therapeutic benefits for a number of medical needs.

Topics: Biomarkers; Biotransformation; C-Reactive Protein; Cardiovascular Diseases; Equol; Estrogen Receptor beta; Female; Humans; Intestines; Isoflavones; Lipoproteins, LDL; Male; Osteoporosis; Phytoestrogens; Prostatic Neoplasms; Risk Factors

Phytoestrogens are polyphenolic secondary plant metabolites that have structural and functional similarities to 17beta-oestradiol and have been associated with a protective effect against hormone-related cancers. Most foods in the UK only contain small amounts of phytoestrogens (median content 21 microg/100 g) and the highest content is found in soya and soya-containing foods. The highest phytoestrogen content in commonly consumed foods is found in breads (average content 450 microg/100 g), the main source of isoflavones in the UK diet. The phytoestrogen consumption in cases and controls was considerably lower than in Asian countries. No significant associations between phytoestrogen intake and breast cancer risk in a nested case-control study in EPIC Norfolk were found. Conversely, colorectal cancer risk was inversely associated with enterolignan intake in women but not in men. Prostate cancer risk was positively associated with enterolignan intake, however this association became non-significant when adjusting for dairy intake, suggesting that enterolignans can act as a surrogate marker for dairy or calcium intake.

Topics: Aged; Animals; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Food Analysis; Humans; Isoflavones; Lignans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Factors; United Kingdom

Worldwide disparities exist between geographic regions with regard to prostate cancer incidence and mortality. Countries in East Asia have lower rates of prostate cancer compared with Western countries such as Canada and the US. Some suggest that dietary differences between the two geographic regions, particularly the higher amount of phytoestrogens consumed in East Asia, is responsible for the difference in prostate cancer incidence. The mechanism of action of the soy isoflavones is incompletely understood, but in regards to prostate carcinogenesis likely involves estrogenic effects, cell cycle inhibition, anti-angiogenesis and induction of apoptosis. Recent clinical studies have provided mixed results with regard to a clear association between prostate cancer and soy consumption. Further studies are needed to understand more clearly the relationship between soy consumption and prostatic diseases.

Topics: Animals; Clinical Trials as Topic; Glycine max; Humans; Male; Phytoestrogens; Prostate; Prostatic Neoplasms

Modern consumer needs have stimulated a vast expansion in the dietary supplement market, in an attempt to improve general well being and prevent, rather than cure, disease. Isoflavones form a large part of this market. Their oestrogenic properties are still largely unknown and must be thoroughly researched to ensure they cause no adverse effects, particularly on hormone-dependent reproductive physiology.. As a result of the increasing availability of phytoestrogens, research into their actions now covers a very wide field, many of which impact on reproductive potential. Time of exposure is crucial, as is interaction with other dietary components. Their putative role as chemoprotective agents has been expanded in recent years which may have an indirect impact on fertility by decreasing mortality rates in both men and women.. Phytoestrogens are still a current research topic in reproduction and fertility. Genistein is a putative therapeutic tool in cancer treatment although this must be considered along with evidence that it may cause DNA damage in sperm, depending on the concentration. The effects of phytoestrogen in the body are not limited to oestrogenic action. Much more epidemiological data are required to interpret current molecular studies, and those of previous years.

Topics: Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fertility; Genistein; Humans; Male; Phytoestrogens; Pregnancy; Prostatic Neoplasms; Reproduction; Spermatozoa

Phytoestrogens are non-steroidal estrogens widely distributed in many kinds of plants. They are natural compounds structurally similar to estrogen and with estrogenic or anti-androgenic activities. Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent and associated with age. Recently, in many epidemiological and experimental researches, it has been reported that phytoestrogens play a role in the prevention and treatment of PCa and BPH. Regulation of sexual hormones, inhibition of cell proliferation, induction of cell apoptosis and anti-oxidation of such plant estrogens may be involved in the mechanisms.

Topics: Animals; Disease Models, Animal; Humans; Male; Phytoestrogens; Prostatic Hyperplasia; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Rats, Wistar

This review focuses on the possible role in human health of the consumption of lignan-rich foods. Most of the plant lignans in human foods are converted by the intestinal microflora in the upper part of the large bowel to enterolactone and enterodiol, called mammalian or enterolignans. The protective role of these compounds, particularly in chronic Western diseases, is discussed. Evidence suggests that fiber- and lignan-rich whole-grain cereals, beans, berries, nuts, and various seeds are the main protective foods. Many factors, in addition to diet, such as intestinal microflora, smoking, antibiotics, and obesity affect circulating lignan levels in the body. Lignan-rich diets may be beneficial, particularly if consumed for life. Experimental evidence in animals has shown clear anticarcinogenic effects of flaxseed or pure lignans in many types of cancer. Many epidemiological results are controversial, partly because the determinants of plasma enterolactone are very different in different countries. The source of the lignans seems to play a role because other factors in the food obviously participate in the protective effects. The results are promising, but much work is still needed in this area of medicine.

Topics: 4-Butyrolactone; Animals; Cardiovascular Diseases; Colorectal Neoplasms; Dietary Fiber; Edible Grain; Endometrial Neoplasms; Feeding Behavior; Female; Health Status; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plants, Edible; Prostatic Neoplasms; Seeds; Vegetables

Prostate cancer (CaP) is second only to lung cancer as the cause of cancer-related deaths in American men and is responsible for over 29,000 deaths per year. One promising approach to reduce the incidence of CaP is through chemoprevention, which has been recognized as a plausible and cost-effective approach to reduce cancer morbidity and mortality by inhibiting precancerous events before the occurrence of clinical disease. Indeed, CaP is an ideal candidate disease for chemoprevention because it is typically diagnosed in the elderly population with a relatively slower rate of growth and progression, and therefore, even a modest delay in the development of cancer, achieved through pharmacologic or nutritional intervention, could result in substantial reduction in the incidence of clinically detectable disease. In this review, we have summarized the recent investigations and mechanistic studies on CaP chemoprevention using dietary agents, such as selenium, vitamins D and E, lycopene, phytoestrogens, flavonoids, and green tea polyphenols. Well-designed trials are required to delineate the potential clinical usefulness of these agents through issues, such as determining the optimal period and route of administration, systemic bioavailability, optimal dosing and toxicity of the agent, and single or combinatorial approach. It is hoped that, combining the knowledge based on agents with targets, effective approaches for CaP chemoprevention can be established.

Topics: Carotenoids; Chemoprevention; Clinical Trials as Topic; Dietary Supplements; Flavonoids; Humans; Lycopene; Male; Phytoestrogens; Prostatic Neoplasms; Selenium Compounds; Vitamin D; Vitamin E

Lignan is an important phytoestrogen with weakly estrogenic and anti-estrogenic properties, and possesses diverse bioactivities, including antioxidation, antitumor and antivirus etc. In particular, it may prevent hormone-dependent diseases, such as breast cancer, prostate cancer and benign prostatic hyperplasia. However, many important scientific problems have not been constrained, whether do the metabolites of lignans from foods have their potential genic toxicity? What are the anticancer mechanisms of lignans? What is the dosage of lignans to achieve the desired biological effect? In this paper, the references on lignans have systematically been reviewed in the following aspects: classification, distribution, metabolism, pharmacological activities and analytical methods, and a prospective of future studies on lignans is also elucidated.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Female; Humans; Lignans; Male; Phytoestrogens; Plants, Medicinal; Prostatic Neoplasms

As alternative medicine gains popularity in the US, a greater understanding of the proven benefits and detriments of the supplements commonly used is needed by physicians. Chemoprevention through the use of supplements or dietary means is one example. Through epidemiological studies, it is clear that there is variation in the geographic incidence of certain cancers. One such variation is in prostate cancer, for which Asian men have a decreased death rate as compared with their Western counterparts. One hypothesis for this reduction in prostate cancer deaths is due to the difference in soy consumption. The purpose of this paper is to review the effects of soy at the molecular level as well as to review the in-vivo effects.. The mechanism by which soy or, more accurately, the isoflavones act is described in this review. Multiple studies attempting to clarify the effects of the isoflavones on molecular pathways will be discussed. Furthermore, recent studies demonstrating the effect of isoflavones on prostate-specific antigen, testosterone, estrogen, and hormone receptor expression in human subjects will be reviewed.. After reading this review, we expect that the reader will understand the background of the isoflavones, the effect they exert at the molecular level, and their proposed benefits and limitations in human patients. However, what will be evident at the conclusion of this manuscript is the need for future studies of the effects of soy in prostate cancer patients.

Topics: Anticarcinogenic Agents; Genistein; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Phytotherapy; Plant Extracts; Prostatic Neoplasms

Phytoestrogens are natural plant substances. The four main classes are isoflavones, flavonoids, coumestans, and lignans. Phytoestrogens have anti-carcinogenic potential. For evaluation of the effect of phytoestrogens on prostate cancer risk, we reviewed analytical epidemiological data.. Up to now, there are few studies that have assessed the direct relation between the individual dietary intake of soy products and other nutrients with phytoestrogens and the risk of prostate cancer. We decided to review analytical epidemiological studies providing data on (a) dietary soy intake or flavonoids intake, (b) urinary excretion of isoflavones or lignans, or (c) blood measurements of isoflavones or lignans. Soy is used as a marker for isoflavone intake.. Overall, the results of these studies do not show protective effects. Only four of these studies are prospective, and none of them found statistically significant prostate cancer reductions. Two prospective studies measured flavonoid intake and one reported a preventive effect on prostate cancer for the assumption of myricetin. One study assessed enterolactone concentrations in three different countries and showed no reduction in prostate cancer occurrence.. Few studies showed protective effect between phytoestrogen intake and prostate cancer risk.

Topics: Age Distribution; Aged; Case-Control Studies; Cross-Sectional Studies; Dietary Supplements; Humans; Incidence; Male; Middle Aged; Neoplasm Staging; Phytoestrogens; Plant Preparations; Prognosis; Prospective Studies; Prostatic Neoplasms; Risk Assessment; Sensitivity and Specificity; Survival Rate

Prostate cancer is poised to become the most prevalent male cancer in the Western world. In Japan and China, incidence rates are almost 10-fold less those reported in the United States and the European Union. Epidemiological data suggest that environmental factors such as diet can significantly influence the incidence and mortality of prostate cancer. The differences in lifestyle between East and West are one of the major risk factors for developing prostate cancer. Traditional Japanese and Chinese diets are rich in foods containing phytoestrogenic compounds, whereas the Western diet is a poor source of these phytochemicals. The lignan phytoestrogens are the most widely occurring of these compounds. In vitro and in vivo reports in the literature indicate that lignans have the capacity to affect the pathogenesis of prostate cancer. However, their precise mechanism of action in prostate carcinogenesis remains unclear. This article outlines the possible role of lignans in prostate cancer by reviewing the current in vitro and in vivo evidence for their anticancer activities. The intriguing concept that lignans may play a role in the prevention and treatment of prostate cancer over the lifetime of an individual is discussed.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Diet; Humans; Life Style; Lignans; Male; Phytoestrogens; Prevalence; Prostatic Neoplasms; Risk Factors

Phytoestrogens are plant-derived hormone-like diphenolic compounds of dietary origin that are present at high levels in plasma of subjects living in areas with low atherosclerosis and cancer incidence. The term phytoestrogen is commonly applied to the soy isoflavones genistein, daidzein and glycitein. As outlined in a previous review article in this journal by Adlercreutz and Mazur 1, these compounds are weakly estrogenic and appear to influence the cardiovascular system, the production, metabolism and biological activity of sex-hormones, as well as malignant cell proliferation, differentiation and angiogenesis. Recently skepticism has developed concerning the true potential of phytoestrogens to beneficially modify these processes. A critical analysis of the early findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects, be it by way of lipid reduction, vasodilation or lipoprotein oxidation. Furthermore, contrasting data have been reported on the potential of phytoestrogens to prevent hormone-dependent cancers (e.g. breast and prostate) and to successfully treat post-menopausal complaints, an indication for which they are widely used. These potentially negative findings have led health authorities in several countries to suggest maximum daily intake levels for phytoestrogens. There is now growing interest in the use of soy products containing low levels of phytoestrogens and in research on other phytoestrogen free legumes such as lupin.

Topics: Breast Neoplasms; Cardiovascular System; Female; Humans; Male; Phytoestrogens; Prostatic Neoplasms

Despite the historical use of estrogens in the treatment of prostate cancer (PCa) little is known about their direct biological effects on the prostate, their role in carcinogenesis, and what mechanisms mediate their therapeutic effects on PCa. It is now known that estrogens alone, or in synergism with an androgen, are potent inducers of aberrant growth and neoplastic transformation in the prostate. The mechanisms of estrogen carcinogenicity could be mediated via induction of unscheduled cell proliferation or through metabolic activation of estrogens to genotoxic metabolites. Age-related changes and race-/ethnic-based differences in circulating or locally formed estrogens may explain differential PCa risk among different populations. Loss of expression of estrogen receptor (ER)-beta expression during prostate carcinogenesis and prevention of estrogen-mediated oxidative damage could be exploited in future PCa prevention strategies. Re-expression of ER-beta in metastatic PCa cells raises the possibility of using ER-beta-specific ligands in triggering cell death in these malignant cells. A variety of new estrogenic/anti-estrogenic/selective estrogen receptor modulator (SERM)-like compounds, including 2-methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. Increasing numbers of patients self-medicate with herbal formulations such as PC-SPES. Some of these compounds are selective ER-beta ligands, while most of them have minimal interaction with ER-alpha. Although many may inhibit testosterone production by blockade of the hypothalamal-pituitary-testis axis, the most effective agents also exhibit direct cytostatic, cytotoxic, or apoptotic action on PCa cells. Some of them are potent in interfering with tubulin polymerization, blocking angiogenesis and cell motility, suppressing DNA synthesis, and inhibiting specific kinase activities. Further discovery of other compounds with potent apoptotic activities but minimal estrogen action should promote development of a new generation of effective PCa preventive or treatment regimens with few or no side-effects due to estrogenicity. Further advancement of our knowledge of the role of estrogens in prostate carcinogenesis through metabolic activation of estrogens and/or ER-mediated pathways will certainly result in better preventive or therapeutic modalities for PCa.

Topics: Estrogen Receptor Modulators; Estrogens; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Receptors, Estrogen

The incidence of hormone-dependent cancers, such as those of the breast and prostate, is much lower in Eastern countries such as China and Japan in comparison with the Western world. Diet is believed to have a major effect on disease risk and one group of compounds, the phyto-oestrogens, which are consumed in large amounts in Asian populations, have been implicated in cancer protection. This view follows the finding that plasma and urinary levels of phyto-oestrogens are much higher in areas where cancer incidence is low in comparison with areas of high cancer incidence. The phyto-oestrogens are comprised of two main groups; the isoflavones and lignans. Of the isoflavones, genistein and daidzein have been the most widely studied. These compounds have been shown to possess anticancer properties; however their precise mechanism of action remains to be elucidated. In comparison, few studies have investigated the effects of lignans in breast and prostate cancer. In vitro studies have shown that genistein exerts biphasic effects on cancer cell growth, stimulating growth at low concentrations (<10 microm) and inhibiting growth at high concentrations (>10 microm), which suggests that low phyto-oestrogen levels may stimulate cancer growth in vivo. Plasma phyto-oestrogen concentrations of >10 microm cannot be achieved by dietary intake and therefore the timing of exposure to phyto-oestrogens may be of the utmost importance in determining their chemopreventive effects. The present paper reviews the effects of phyto-oestrogens on breast and prostate cancer in vivo and in vitro and discusses possible mechanisms of action via which these compounds may exert their effects.

Topics: Animals; Breast Neoplasms; Cell Division; Diet; Female; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms; Tumor Cells, Cultured

Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH)(2)-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1 alpha-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-beta (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 micromol/L. The high concentration of 50 micromol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.

Topics: Animals; Breast Neoplasms; Carcinoma; Colorectal Neoplasms; Diet; Female; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Vitamin D

Recent results obtained in collaboration with many other groups with regard to phytoestrogens (isoflavones and lignans) and breast cancer, prostate cancer and cardiovascular disease are presented and discussed in light of new developments in the field. Both isoflavones and lignans may be protective with regard to these diseases, but we do not yet understand some of the controversial results obtained. In this short communication the possible mechanisms of disease prevention were not discussed.

Topics: Anticarcinogenic Agents; Cardiotonic Agents; Cardiovascular Diseases; Edible Grain; Fruit; Humans; Male; Phytoestrogens; Prostatic Neoplasms; Vegetables

Estrogens have previously been extensively used in prostate cancer treatment. Serious side effects, primarily in cardiovascular system have, however, limited their use. The therapeutic effect of estrogen in preventing prostate cancer growth was mainly obtained indirectly by feedback inhibition of the hypothalamic release of LRH leading to lowered serum androgen levels and castration like effects. Prostate tissue is also most probably a target for direct regulation by estrogens. Prostate contains estrogen receptor alpha (ERalpha) and beta (ERbeta), which are localized characteristically in stroma and epithelium, respectively. The physiological function of these receptors is not known but there is evidence of the role of estrogens in prostatic carcinogenesis. Developing prostate seems particularly sensitive to increased level of endogenous and/or exogenous estrogens. Perinatal or neonatal exposure of rats and mice to estrogens leads to "imprinting" of prostate associated with increased proliferation, inflammation and dysplastic epithelial changes later in life. Prolonged treatment of adult rodents with estrogens along with androgens also leads to epithelial metaplasia, PIN-like lesions and even adenocarcinoma of prostate speaking for the role of estrogen in prostate cancer development. Recent results concerning antiestrogen inhibition of prostate cancer development beyond PIN-type lesions in transgenic mouse models further suggests a role for estrogens in prostate cancer progression. These results also suggest that direct inhibition of estrogen action at the level of prostate tissue may provide an important novel principle of development of prostate cancer therapies.

Topics: Animals; Cell Proliferation; Estrogen Receptor Modulators; Estrogens; Gene Expression; Humans; Male; Mice; Mice, Knockout; Organogenesis; Phytoestrogens; Prolactin; Prostatic Neoplasms; Receptors, Estrogen; Selective Estrogen Receptor Modulators

Vitamin D deficiency increases risk of prostate cancer. According to our recent results, the key Vitamin D hormone involved in the regulation of cell proliferation in prostate is 25(OH) Vitamin D3. It is mainly acting directly through the Vitamin D receptor (VDR), but partially also through its 1alpha-hydroxylation in the prostate. A deficiency of 25(OH) Vitamin D is common especially during the winter season in the Northern and Southern latitudes due to an insufficient sun exposure, but Vitamin D deficient diet may partially contribute to it. A lack of Vitamin D action may also be due to an altered metabolism or Vitamin D resistance. Vitamin D resistance might be brought up by several mechanisms: Firstly, an increased 24-hydroxylation may increase the inactivation of hormonal Vitamin D metabolites resulting in a Vitamin D resistance. This is obvious in the cancers in which an oncogenic amplification of 24-hydroxykase gene takes place, although an amplification of this gene in prostate cancer has not yet been described. During the aging, the activity of 24-hydroxylase increases, whereas 1alpha-hydroxylation decreases. Furthermore, it is possible that a high serum concentration of 25(OH)D3 could induce 24-hydroxylase expression in prostate. Secondly, Vitamin D receptor gene polymorphism or defects may result in a partial or complete Vitamin D resistance. Thirdly, an overexpression or hyperphosphorylation of retinoblastoma protein may result in an inefficient mitotic control by Vitamin D. Fourthly, endogenous steroids (reviewed by [D.M. Peehl, D. Feldman, Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer, J. Steroid Biochem. Mol. Biol. (2004)]) and phytoestrogens may modulate the expression of Vitamin D metabolizing enzymes. In summary, the local metabolism of hormonal Vitamin D seems to play an important role in the development and progression of prostate cancer.

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Calcifediol; Calcitriol; Cell Proliferation; Cholecalciferol; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Gene Expression Regulation, Neoplastic; Humans; Male; Phytoestrogens; Prostate; Prostatic Neoplasms; Receptors, Calcitriol; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase

The prostate has only one function, namely to secrete fluid containing substances that are needed for reproduction. This requires an extremely high concentration of androgens in the tissues. Benign prostatic hypertrophy (BPH) seems to be related to the long-term exposure of the prostate to the strong androgen 5alpha-dihydrotestosterone (DHT) and, possibly, to estrogens. The relation between prostate cancer and androgens is suggested to be U-shaped, with both extremes of androgen concentrations being associated with increased risk of invasive cancer. In the treatment of patients with BPH, the lipidic liposterolic extracts of Serenoa repens were as effective as the pharmaceutical inhibitors of the 5alpha-reductase enzyme or alpha1-adrenergic blockers in relieving urinary symptoms. In addition to moderately inhibiting the 5alpha-reductase activity, Serenoa seems to exert anti-inflammatory and complementary cellular actions with beneficial effects on the prostate. Unlike the pharmaceutical 5alpha-reductase inhibitors, finasteride and dutasteride, Serenoa does not suppress serum PSA, facilitating the follow-up and the early detection of prostate cancer. We suggest a strategy to prevent prostate cancer that aims at providing men with partial androgen deficiency correct testosterone substitution with a sustained release buccal bio-adhesive tablet. In addition, food supplementation with extracts of Serenoa repens and a combination of the antioxidants selenium, (cis)-lycopene and natural vitamin E, together with fish oil rich in long-chain polyunsaturated essential fatty acids of the omega-3 group seems warranted. Clearly, a holistic approach including careful clinical and biological monitoring of the aging man and his prostate remains mandatory.

Topics: Aged; Androgen Antagonists; Androgens; Antioxidants; Hormone Replacement Therapy; Humans; Male; Phytoestrogens; Phytotherapy; Plant Preparations; Prostatic Hyperplasia; Prostatic Neoplasms; Serenoa

Androgcns are required to maintain the integrity of the prostate and the survival of androgen dependent epithelial cells within the gland. Anti-androgens arc the primary treatment strategy for non-localized prostate cancer, but ultimately fail over time with the development of androgen independent tumors. Estrogens affect the growth and development of the prostate and may affect the development of prostate cancer. Because of the side effects of estrogen treatment alternative therapies include the use of phytoestrogens as chemopreventative and chemotherapeutic treatment modalities. Phytoestrogens, can cause growth arrest and in some cases apoptosis in prostate cancer cells in vivo and in vitro. This may be due to the estrogenic properties of the compounds or alternative mechanisms of action. A number of phytoestrogens have been shown to have anti-androgenic effects and anti-oxidant activities. Other mechanisms include inhibition of 5alpha-reductase, 17beta-hydroxysteroid dehydrogenase, aromatase, tyrosine specific protein kinases and DNA topoisomerase II. This review examines the possible relation between phytoestrogens and prostate cancer and their possible use in prostate cancer prevention or management.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Disease Models, Animal; Estradiol; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Mice; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Receptors, Estrogen

Phyto-oestrogens are oestrogenic compounds found in plants and consist of isoflavones, lignans and coumestans. Epidemiological studies provide evidence for a protective role of isoflavones, and to a lesser extent lignans, against the development of numerous chronic diseases, including several cancers, cardiovascular disease and osteoporosis. The structural similarity of phyto-oestrogens to endogenous oestrogens has prompted the hypothesis that phyto-oestrogens exert hormonal or anti-hormonal effects relevant to the risk of hormone-dependent disease and/or their suitability as a dietary alternative to hormone replacement therapy. The many human studies that have evaluated the effects of isoflavones and lignans on various endpoints relating to risk of various diseases have greatly increased knowledge of how these compounds behave. At the same time, additional questions have been generated. For example, the increasing interest in extracting isoflavones from the soybean for incorporation into dietary supplements has raised important concerns regarding safety and efficacy. Overall, it is clear that phyto-oestrogens are an area of active and advancing research with great potential to continue to affect human health.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cardiovascular Diseases; Female; Humans; Isoflavones; Male; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms

Phytoestrogens are defined to be plant chemicals that modify estrogenic effects in the body by binding to the estrogen receptors in mammals. Isoflavones, coumestane, lignan, and prenylflavones are examples of these, with isoflavones from soy foods and lignans from rye being a major dietary contribution. Mechanisms of cancer prevention by these phytoestrogens are reviewed, and human epidemiological studies, especially for breast and prostate cancers, are summarized and the results discussed.

Topics: Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk; Soybean Proteins

Prostate cancer is the first neoplasia in the United States accounting the second in cancer deaths. With all the treatments strategies in debate because of their side effects, is very important try to elucidate prevention mechanisms that may be implicate in the development of this disease, between these, nutrients have been of mayor importance. In the present review we tried to study the most important nutritional factors implicated in the development and prevention of prostate carcinoma. We focus our attention over the polyphenols of the red wine, which influence over cellular proliferation and apoptosis in LNCaP cells have been studied in our Department.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Diet; Dietary Fats; Estrogens, Non-Steroidal; Flavonoids; Humans; Incidence; Isoflavones; Male; Phenols; Phytoestrogens; Plant Preparations; Polymers; Polyphenols; Prostatic Neoplasms; Spain; Tumor Cells, Cultured; United States; Vitamins; Wine

Epidemiological data of phytoestrogens and prostate cancer strongly supports the cancer protective effects of isoflavones found in soy products. Inhibition of cell proliferation via hormone-dependent and hormone-independent mechanisms by soy phytochemicals has been studied extensively in cell culture and animal studies. Herein, we review the current literature on the epidemiology and effects of two soy phytoestrogens, genistein and daidzein, and would stress the need for controlled human trials to assess the true preventive and therapeutic effects of these compounds.

Topics: Animals; Disease Models, Animal; Estrogens, Non-Steroidal; Genistein; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Rats, Wistar; Signal Transduction

This article is designed to help nursing professionals advise patients about the role of soy in the prevention and treatment of heart disease, breast cancer, and prostate cancer. Soy protein lowers total cholesterol, low-density lipoprotein cholesterol, and triglycerides in humans and inhibits atherosclerosis in animals. In cell culture studies and animal research, the soy isoflavone genistein offers protection from breast cancer and prostate cancer because it prevents cancer initiation, slows promotion, and impedes cancer progression. This article synthesizes the current research concerning soy phytoestrogens and the prevention and treatment of heart disease, breast cancer, and prostate cancer. Nursing professionals may use this information when counseling patients.

Topics: Animals; Arteriosclerosis; Breast Neoplasms; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Hypercholesterolemia; Isoflavones; Male; Patient Education as Topic; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; Soybean Proteins

Topics: Antioxidants; Ascorbic Acid; Carotenoids; Diet; Dietary Fats; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Meat; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms; Selenium; Tocopherols; Vitamin A; Vitamin D; Vitamin E

Phytoestrogens have been investigated at the epidemiological, clinical and molecular levels to determine their potential health benefits. The two major groups of phytoestrogens, isoflavones and lignans, are abundant in soy products and flax respectively, but are also present in a variety of other foods. It is thought that these estrogen-like compounds may protect against chronic diseases, such as hormone-dependent cancers, cardiovascular disease and osteoporosis. Furthermore, phytoestrogens are used as a natural alternative to hormone replacement therapy and to reduce menopausal symptoms. Phytoestrogens have been shown to induce both estrogenic and anti-estrogenic effects but their biological relevance and potency have not been well characterized. In children, consumption of soy-based formulas and soy milk can lead to high levels of exposure to phytoestrogens with only limited data available concerning potential benefits or adverse effects. Phytoestrogens are considered good candidates for use in natural therapies and as chemopreventive agents in adults. Safe and efficacious levels have yet to be established.

Topics: Biological Availability; Breast Neoplasms; Cardiovascular Diseases; Diet; Estrogens, Non-Steroidal; Female; Food Analysis; Humans; Isoflavones; Lignans; Male; Menopause; Osteoporosis; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms

Topics: Alcohol Drinking; Breast Neoplasms; Diet, Fat-Restricted; Estrogens, Non-Steroidal; Exercise; Female; Fruit; Health Promotion; Humans; Isoflavones; Male; Obesity; Phytoestrogens; Plant Preparations; Primary Prevention; Prostatic Neoplasms; Vegetables

Phyto-oestrogens have been suggested to have a preventive effect against various cancers. This review includes a discussion of the consumption of phyto-oestrogen-rich foods such as soy, a source of isoflavones, and whole grain products, which contain lignans, and their role in the prevention of breast, prostate, and colon cancer. In women, a soy-containing diet is only slightly protective against breast cancer, if at all, but is more likely to be beneficial if initiated before puberty or during adolescence. These findings are supported by conclusions of studies of immigrants and other epidemiological studies. However, in one case-control study and one prospective study, a low-lignan diet increased the risk of breast cancer. Experimental evidence also exists for an inhibitory effect of soy and rye bran on prostate-cancer growth and for rye bran or isolated lignans on colon cancer. Whether these observed protective effects are caused by the presence of dietary phyto-oestrogens, or whether they are merely indicators of a healthy diet in general, has not been established.

Topics: 4-Butyrolactone; Animals; Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lignans; Male; Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

Nutrition is apparently a major risk factor for the development and progression of prostate cancer. Based on experimental studies and epidemiologic data mainly from case-control studies or cohort studies, there is strong evidence that reduction of the total energy consumption, a diet comprising less than 30% fat, and increased intake of phytoestrogens, vitamins D and E and selenium could yield a decreased prostate cancer incidence. Furthermore, some of these measures appear to have antitumoral capacity even in the presence of the disease. These observations have provided a rationale to forward large prospective trials on dietary interventions to prove the efficacy of the concept and further delineate the correlation between nutritional compounds and prostate cancer risk. These chemoprevention trials are either aiming a reduction prostate cancer incidence or a decrease in tumor progression. Depending on the study design, large numbers of individuals need to be enrolled and long follow-up intervals are required thus making such trials highly complex and cost-intensive. However, regarding the potential relevance of chemoprevention on public health, further efforts to identify nutritional factors affecting prostate cancer growth are warranted.

Topics: Carotenoids; Diet; Dietary Fats; Estrogens, Non-Steroidal; Humans; Isoflavones; Lycopene; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Selenium; Vitamins

Topics: Breast Neoplasms; Endometrial Neoplasms; Epidemiologic Studies; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lung Neoplasms; Male; Neoplasms; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; Stomach Neoplasms

One of the problems which may beset epidemiological studies is the difficulty of accurately measuring the dietary intakes of participants. Biomarkers of diet promise to provide a more accurate measure of dietary intake and a more objective one in that they are not reliant on the subject's memory. This review considers some issues of importance in epidemiology when information is obtained from biomarkers. The approach taken is to use examples both of normal dietary constituents and of contaminants in relation to a range of diet and health questions to illustrate these points. A brief overview of the role of sample collection, processing and storage is given including some generic recommendations for maximising the reliability of subsequent analytical data. Using the examples of phytoestrogens and iodine the question of whether biomarkers can accurately reflect the intake of the dietary constituents of interest at the population level or at the individual level is considered. The relationship of the biomarker to the natural history of the disease is exemplified using the role of folate in neural tube defects. Finally, intakes of vitamin D and heterocyclic amines are used to illustrate the integration of biomarkers into epidemiological studies of prostate and colorectal cancer, respectively. It is concluded that biomarkers may provide a more accurate and objective measure of diet than estimates of current or usual intake but that this approach also has limitations. A combination of methods will probably prove to be most valuable and this approach is being taken in current large prospective studies.

Topics: Biomarkers; Colorectal Neoplasms; Cooking; Diet; Epidemiologic Factors; Estrogens, Non-Steroidal; Female; Folic Acid; Genetic Predisposition to Disease; Genistein; Health Surveys; Heterocyclic Compounds; Humans; Iodine; Isoflavones; Male; Meat; Middle Aged; Neural Tube Defects; Nutritional Status; Phytoestrogens; Plant Preparations; Predictive Value of Tests; Pregnancy; Prostatic Neoplasms; Risk Factors; Specimen Handling; Vitamin D

Phytoestrogens, plant chemicals classified as isoflavones, coumestans and lignans, display estrogen-like activity because of their structural similarity to human estrogens and exhibit high affinity binding for the estrogen receptor beta. They are common components of food items such as grains, beans, fruits and nuts. Isoflavones are primarily found in soybeans and foods made from soy. In particular, significant therapeutic properties have been generally attributed to soy isoflavones, but most of the claims have been poorly, or not at all, confirmed by well designed clinical trials. Such is the case of the purported role of soy isoflavones in reducing plasma cholesterol levels. This link is now not supported by many authors or by appropriately designed clinical studies. The role of isoflavones in cancer prevention, particularly of tumours under endocrine control (breast, prostate and others) is again only supported by weak to nonexisting clinical evidence. A similarcase is that of the prevention/treatment of postmenopausal symptoms and osteoporosis. Disturbing data have been reported on potential negative effects of soy isoflavones on cognitive function in the aged, particularly relating to tofu intake. Recent studies have finally indicated a potential role for soy isoflavones in inducing chromosomal changes in cells exposed in vitro and potentiating chemical carcinogens. These findings may not, however, be extrapolated to clinical conditions. Available data do not appear to unequivocally support beneficial effects of soy isoflavones, and warn against their wide use, in the absence of satisfactory clinical findings.

Topics: Adult; Animals; Breast Neoplasms; Cardiovascular Diseases; Cholesterol; Climacteric; Cognition; Diet; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Soybean Proteins

Topics: Animals; Diet; Estrogens, Non-Steroidal; Finland; Humans; Isoflavones; Japan; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Soybean Proteins; United States

Chemoprevention of prostate cancer is the administration of agents to prevent, inhibit, or delay progression of prostate cancer. Asian men have a much lower incidence of prostate cancer than men in Europe or the USA. Asian food includes low-fat, high-fiber diets, which provide a rich supply of weak dietary estrogens. These estrogens have been proposed as chemopreventive agents. In addition to their estrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability and can also inhibit enzymes, such as tyrosine kinase or topoisomerase, which are important for cellular proliferation. In addition, nutritional factors such as reduced fat intake, vitamin E, vitamin D, and selenium may have a protective effect against prostate cancer. The fact was proven in large epidemiological studies as well as experimental observations. In the animal model, the progression of established tumors can be inhibited by these agents. A number of studies to investigate the effect of possible chemopreventive agents for men at high risk of prostate cancer are established. End points for evaluation are mainly based on changes in PSA, changes of histological precursors, or time of onset of clinical disease. The concept of chemoprevention in prostate cancer might have a significant impact on the incidence and mortality of this disease.

Topics: Animals; Antineoplastic Agents, Phytogenic; Estrogens, Non-Steroidal; Feeding Behavior; Humans; Isoflavones; Life Style; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors

The primary prevention of prostate cancer through nutritional modification is becoming a focus of attention as important relationships between diet and cancer are becoming evident. Relevant research is reviewed, along with recent data implicating various vitamin supplements and food products in the prevention and treatment of prostate cancer.. The epidemiology of prostate cancer, and current knowledge of prevention, screening, and progression of neoplasia is discussed. The current understanding of diet and its importance in primary and secondary prevention is explored. Literature searches were performed on MedLine using relevant keywords to find studies relating to prevention and treatment of prostate cancer using dietary methods. Of these, 104 published manuscripts were used. The search was limited from the year 1975 to the present.. Incidence rates for prostate cancer vary according to diet and lifestyle. Several double-blind placebo-controlled clinical trials have shown that supplementation with selenium reduces cancer incidence. Inhibitory effects on the growth of in vitro prostate cancer cell lines have been observed with the administration of soy isoflavones, lycopenes from tomatoes, and vitamin D. Other compounds, such as calcium and fatty acids, have been linked to higher incidences of prostate cancer.. Evidence exists that diet may play an important role in the primary prevention of prostate cancer. Further research is necessary to define the role that nutrition plays in the prevention or promotion of prostate cancer.

Topics: Calcium, Dietary; Carotenoids; Estrogens, Non-Steroidal; Fatty Acids; Humans; Isoflavones; Male; Nutritional Physiological Phenomena; Phytoestrogens; Plant Preparations; Plants, Edible; Prostatic Neoplasms; Selenium; Soybean Proteins; Vegetables; Vitamin D; Vitamin E

Population-based studies from around the world support the theory that soy products and their constituents, primarily the isoflavones or phytoestrogens, are partly responsible for the lower rates of certain chronic diseases in different areas of the world. Cardiovascular disease and hormonally induced cancers are just a few of the conditions lower in Asian countries that consume large quantities of soy per average person. Genistein, one of soy's individual phytoestrogens, has been found to inhibit numerous breast and prostate cancer cell lines. A limited amount of clinical evidence also points to a beneficial role of soy in reducing hormonal levels and exhibiting weak estrogen and antiestrogen-like qualities. Other phytoestrogens found in nature, such as lignans, may also have a future role in cancer. Collectively, these phytoestrogens, like genistein, have enough evidence to warrant their use in a number of clinical trials as a potential chemopreventive agent or adjunct to prostate cancer treatment.

Topics: Breast Neoplasms; Cardiovascular Diseases; Chemoprevention; Chronic Disease; Epidemiologic Methods; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Phytotherapy; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

Topics: Animals; Apoptosis; Cell Division; Diet; Estrogens; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostate; Prostatic Neoplasms; Signal Transduction

Epidemiological studies suggest that diets rich in phytoestrogens (plant estrogens), particularly soy and unrefined grain products, may be associated with low risk of breast and prostate cancer. It has also been proposed that dietary phytoestrogens could play a role in the prevention of other estrogen-related conditions, namely cardiovascular disease, menopausal symptoms and post-menopausal osteoporosis. However, there is no direct evidence for the beneficial effects of phytoestrogens in humans. All information is based on consumption of phytoestrogen-rich diets, and the causal relationship and the mechanisms of phytoestrogen action in humans still remain to be demonstrated. In addition, the possible adverse effects of phytoestrogens have not been evaluated. It is plausible that phytoestrogens, as any exogenous hormonally active agent, might also cause adverse effects in the endocrine system, i.e. act as endocrine disrupters.

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Diet; Endocrine Glands; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Receptors, Estrogen

Epidemiological studies have revealed that high levels of lignans and isoflavonoids are frequently associated with low breast, prostate and colon cancer risk, as well as a low risk of coronary heart disease. These compounds seem to be cancer protective and/or are biomarkers of a 'healthy' diet. All soy protein products consumed by Asian populations have high concentrations of isoflavonoids. In other countries, such as Finland and Sweden, the lignan levels are higher in populations with the lowest risk because of a high consumption of whole-grain rye bread, berries and some vegetables. There is a strong association between fibre intake per kilogram body weight and lignan concentrations in body fluids. Breast cancer has been found to be associated with low lignan levels in the USA, Finland, Sweden and Australia. With regard to prostate and colon cancer, as well as coronary heart disease, the epidemiological data related to phytoestrogens are still very limited.

Topics: Breast Neoplasms; Coronary Disease; Diet; Epidemiology; Estrogens, Non-Steroidal; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms

Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2-3%. Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.

Topics: Estrogens, Non-Steroidal; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Prostatic Diseases; Prostatic Hyperplasia; Prostatic Neoplasms

Reliable and adequate animal models are required, not only for investigation of etiology, pathogenesis, and treatment of prostate cancer, but also for chemoprevention of prostatic carcinogenesis.. Animal models for the study of premalignant changes in the prostate are reviewed in the paper, with specific reference to the neonatally estrogenized mouse model.. Neonatal treatment of newborn Han:NMRI mice with synthetic non-steroidal estrogen, diethylstilbestrol (DES; 2 micrograms/pup on days 1-3 after birth) promoted hyperplastic and dysplastic changes in the periurethral region of the prostate at the age of 9-18 months. Dietary soy partially inhibited the development of prostatic dysplasia in these neonatally estrogenized animals, which may be due to phytoestrogens contained in soy-rich food.. Prostatic cancer and its possible precursors develop spontaneously, or can be induced by different chemical and hormonal manipulations in certain animal species and strains. Neonatal estrogenization of the mouse results in prostatic dysplasia, which can be partially prevented by dietary soy. There are morphological similarities between human prostatic intraepithelial neoplasia (PIN) and dysplastic changes in rodent prostates, but more data is needed before these dysplastic lesions can be considered equivalent to human PIN.

Topics: Animals; Animals, Newborn; Diet; Diethylstilbestrol; Disease Models, Animal; Estrogens, Non-Steroidal; Glycine max; Isoflavones; Male; Mice; Phytoestrogens; Plant Preparations; Prostate; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Rats; Rats, Inbred F344

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Diet, Vegetarian; Dietary Fats; Dietary Fiber; Endometrial Neoplasms; Estrogens; Estrogens, Non-Steroidal; Female; Gonadal Steroid Hormones; Humans; Incidence; Isoflavones; Lignans; Lignin; Male; Menopause; Ovarian Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors

Phytoestrogens have been suggested to have an anti-proliferative role in prostate cancer, potentially by acting through estrogen receptor beta (ERβ) and modulating several hormones. We primarily aimed to investigate the effect of a phytoestrogen intervention on hormone concentrations in blood depending on the ERβ genotype. Patients with low and intermediate-risk prostate cancer, scheduled for radical prostatectomy, were randomized to an intervention group provided with soybeans and flaxseeds (∼200 mg phytoestrogens/d) added to their diet until their surgery, or a control group that was not provided with any food items. Both groups received official dietary recommendations. Blood samples were collected at baseline and endpoint and blood concentrations of different hormones and phytoestrogens were analyzed. The phytoestrogen-rich diet did not affect serum concentrations of testosterone, insulin-like growth factor 1, or sex hormone-binding globulin (SHBG). However, we found a trend of decreased risk of increased serum concentration of estradiol in the intervention group compared to the control group but only in a specific genotype of ERβ (

Topics: Estradiol; Estrogen Receptor beta; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Testosterone

A high intake of phytoestrogens, found in soy, rye, and seeds, is associated with a reduced risk of a prostate cancer diagnosis. Previously, we found that the overall decreased risk of prostate cancer diagnosis in males with a high intake of phytoestrogens was strongly modified by a nucleotide sequence variant in the estrogen receptor-beta (ERβ) gene. However, we do not know if phytoestrogens can inhibit the growth of prostate cancer in males with established diseases. If there is an inhibition or a delay, there is reason to believe that different variants of the ERβ gene will modify the effect. Therefore, we designed an intervention study to investigate the effect of the addition of foods high in phytoestrogens and their interaction with the ERβ genotype on prostate tumor proliferation in patients with prostate cancer.. The PRODICA trial is a randomized ongoing intervention study in patients with low- and intermediate-risk prostate cancer with a Gleason score < 8, prostate-specific antigen (PSA) < 20, and scheduled for radical prostatectomy. The study is conducted at Sahlgrenska University Hospital in Gothenburg, Sweden. The intervention consists of a daily intake of soybeans and flaxseeds (~ 200 mg of phytoestrogens) until the surgery, approximately 6 weeks. The aim is to recruit 200 participants. The primary outcome is the difference in the proliferation marker Ki-67 between the intervention and the control groups. The genotype of ERβ will be investigated as an effect-modifying factor. Secondary outcomes include, e.g., concentrations of PSA and steroid hormones in the blood.. The results of the PRODICA trial will contribute important information on the relevance of increasing the intake of phytoestrogens in patients with prostate cancer who want to make dietary changes to improve the prognosis of their cancer. If genetic factors turn out to influence the effect of the intervention diet, dietary advice can be given to patients who most likely benefit from it. Dietary interventions are cost-effective, non-invasive, and result in few mild side effects. Lastly, the project will provide basic pathophysiological insights which could be relevant to the development of treatment strategies for patients with prostate cancer.. gov NCT02759380. Registered on 3 May 2016.

Topics: Biomarkers, Tumor; Cell Proliferation; Estrogen Receptor beta; Humans; Male; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Sweden

Specific estrogen metabolites may initiate and promote hormone-related cancers. In epidemiological studies, significantly lower excretion of urinary estradiol (E2) and lower ratio of urinary 2-hydroxy estrogens to 16alpha-hydroxyestrone (2:16 OH-E1) have been reported in prostate cancer cases compared to controls. Although soy supplementation has been shown to increase the ratio 2:16 OH-E1 in women, no studies to our knowledge have investigated the effects of soy supplementation on estrogen metabolism in men. The objective of this randomized controlled trial was to determine the effects of soy protein isolate consumption on estrogen metabolism in men at high risk for developing advanced prostate cancer. Fifty-eight men supplemented their habitual diets with 1 of 3 protein isolates: 1) isoflavone-rich soy protein isolate (SPI+) (107 mg isoflavones/d); 2) alcohol-washed soy protein isolate (SPI-) (<6 mg isoflavones/d); or 3) milk protein isolate (MPI), each providing 40 g protein/d. At 0, 3, and 6 mo of supplementation, the urinary estrogen metabolite profile was measured by GC-MS. Both soy groups had higher E2 excretion than the MPI group at 3 and 6 mo. After 6 mo of supplementation, the SPI+ group had a significantly higher urinary 2:16 OH-E1 ratio than the MPI group. Increased urinary E2 excretion and 2:16 OH-E1 ratio in men consuming soy protein isolate are consistent with studies in postmenopausal women and suggest that soy consumption may be beneficial in men at high risk of progressing to advanced prostate cancer as a result of effects on endogenous estrogen metabolism.

Topics: Aged; Estrogens; Humans; Hydroxyestrones; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Soybean Proteins

Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Dietary Supplements; Double-Blind Method; Estradiol; Humans; Isoflavones; Male; Middle Aged; Neoplasm Staging; Phytoestrogens; Prostatic Neoplasms; Safety; Sex Hormone-Binding Globulin; Testosterone; Treatment Outcome

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Estradiol; Humans; Isoflavones; Male; Middle Aged; Neoplasm Staging; Phytoestrogens; Prostatic Neoplasms; Safety; Testosterone; Treatment Outcome

Phytoestrogens have been suggested to reduce the risk of prostate cancer (CaP), but no data exists on how oral phytoestrogen supplementation influences phytoestrogen concentrations in prostate tissue.. Forty men with CaP, assigned for radical prostatectomy, received 240 mg of clover phytoestrogens or placebo daily for a 2-week period before their operation in a prospective and randomized study. Phytoestrogens were measured in plasma and prostate tissue by time-resolved fluoroimmunoassay (TR-FIA).. All patients had low baseline phytoestrogen concentrations and only 35% had a detectable plasma concentration of equol. Oral supplementation with phytoestrogens induced a statistically significant (P<0.001) 23- and 7-fold increase in prostate tissue concentrations of the phytoestrogens genistein and daidzein, respectively. Supplemented patients demonstrated prostate tissue genistein and daidzein concentrations that were over twofold higher than their plasma. Interestingly, even though the placebo group did not receive phytoestrogen challenge, they also demonstrated twofold prostate tissue genistein and daidzein concentrations compared to their plasma values, suggesting that the prostate can concentrate available phytoestrogens. In addition, after the supplementation, 90% of the supplemented patients had a detectable plasma equol concentration.. We conclude that prostate tissue can concentrate genistein and daidzein. Significant elevation of intraprostatic genistein and daidzein concentrations can be achieved with a short-term dietary phytoestrogen supplementation.

Topics: Administration, Oral; Aged; Dietary Supplements; Genistein; Humans; Isoflavones; Male; Middle Aged; Phytoestrogens; Phytotherapy; Placebos; Prostatectomy; Prostatic Neoplasms

Here we evaluate the effects of oral phytoestrogen supplementation on hypothalamic-pituitary-testicular (HPT) axis in CaP patients.. We recruited 40 men about to undergo radical prostatectomy for CaP to receive either 240 mg of clover phytoestrogens or placebo daily for 2 weeks. Serum hormone levels were measured before and after treatment. In addition, recombinant cell bioassay was used to measure serum androgen bioactivity (ABA).. Phytoestrogen treatment increased serum LH from mean of 3.4-5.2 IU, P = 0.03. Concomitantly, non-significant trend towards decline in serum T, cfT and ABA values was noted. However, mean serum LH/T ratio was upregulated from 0.20 to 0.48 IU/nM, P = 0.004, suggesting compensated hypogonadism. During the course of treatment, serum concentration of equol correlated strongly with the concomitant decrease in ABA (r = -0.586, P = 0.022).. Phytoestrogen treatment interferes with HPT axis in CaP patients by inducing testicular resistance to LH and compensated hypogonadism.

Topics: Administration, Oral; Aged; Androgens; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hypogonadism; Hypothalamus; Luteinizing Hormone; Male; Middle Aged; Phytoestrogens; Pituitary Gland; Prospective Studies; Prostatic Neoplasms; Testis; Testosterone

A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Genistein; Glycine max; Half-Life; Humans; Isoflavones; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Safety; Treatment Outcome

To determine the effects of diets rich in soy and linseed compared with a control diet on biochemical markers of prostate cancer in men diagnosed with prostate cancer.. Twenty-nine men diagnosed with prostate cancer and scheduled to undergo a radical prostatectomy were randomized to one of three groups: soy (high phytoestrogen), soy and linseed (high phytoestrogen), or wheat (low phytoestrogen). A bread was specially manufactured to incorporate 50 g of heat-treated (HT) soy grits or 50 g of HT soy grits and 20 g of linseed as part of the study participant's daily diet. Baseline and preoperative levels of prostate-specific antigen (PSA), free PSA, testosterone, sex hormone-binding globulin, free androgen index, and dihydrotestosterone were measured.. Statistically significant differences were detected between the HT soy grits group and the control wheat group for the percentage of change in total PSA (-12.7% versus 40%, P = 0.02) and the percentage of change in free/total PSA ratio (27.4% versus -15.6%, P = 0.01); and between the HT soy grits group and the HT soy grits and linseed group for the percentage of change in free androgen index (16.4% versus -15.5%, P = 0.04) and the percentage of change in free/total PSA ratio (27.4% versus -10%, P = 0.007).. The data from this study indicate that a daily diet containing four slices of a bread rich in HT soy grits favorably influences the PSA level and the free/total PSA ratio in patients with prostate cancer. This work provides some evidence to support epidemiologic studies claiming that male populations who consume high phytoestrogen diets have a reduced risk of prostate cancer development and progression.

Topics: Adenocarcinoma; Aged; Androgens; Biomarkers, Tumor; Bread; Dihydrotestosterone; Double-Blind Method; Flax; Genistein; Gonadal Steroid Hormones; Humans; Isoflavones; Male; Middle Aged; Neoplasm Proteins; Phytoestrogens; Phytotherapy; Prostate-Specific Antigen; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Soy Foods; Testosterone

Whilst analyzing the morphological effects of a 3-week dietary intervention in patients with prostate cancer, we made an unexpected observation to the effect that prostate biopsy trauma may, at least transiently, increase prostate tumor cell proliferation. Further studies are needed to evaluate the clinical significance of this observation.

Topics: Biopsy, Needle; Cell Division; Dietary Supplements; Double-Blind Method; Estrogens, Non-Steroidal; Follow-Up Studies; Humans; Isoflavones; Male; Neoplasm Invasiveness; Phytoestrogens; Pilot Projects; Plant Preparations; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Assessment; Treatment Outcome

Phytoestrogens may have potential effects on hormone-related cancers (HRC) and cancer biomarkers, but the findings have been inconsistent so far. Participants from the National Health and Nutrition Examination Survey 1999-2010 with information on the levels of urinary phytoestrogens, serum cancer biomarkers and cancer history were included. Sampling-weighted logistic regression models examined the association between urinary phytoestrogens concentrations (creatinine-standardised and log-transformed) and HRC, followed by stratified analyses by race/ethnicity, age and menopausal status for different gender. Correlation analyses between phytoestrogens and cancer biomarkers were performed. Of the total 8844 participants, there were 373 with HRC. We observed total isoflavone and enterodiol excretion were positively associated with HRC, especially in non-Hispanic white female subpopulations (

Topics: Biomarkers, Tumor; Humans; Isoflavones; Lignans; Male; Nutrition Surveys; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms

Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERβ agonists together with abiraterone should be considered as a treatment that might sustain expression of ERβ and offer some benefit to patients.

Topics: Active Transport, Cell Nucleus; Androgen Antagonists; Androstenes; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biopsy; Cell Nucleus; Cohort Studies; ErbB Receptors; Estrogen Receptor beta; Finasteride; Humans; Male; Mice; Mice, Knockout; Neoplasm Grading; Nitriles; Phenylthiohydantoin; Phytoestrogens; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; PTEN Phosphohydrolase; Receptors, Androgen; Receptors, Estrogen

Phytoestrogens (PEs) have estrogen-like activity and were found to lower incidences of several hormone-dependent cancers. Emerging evidence suggests that estrogen may play a role in lung cancer carcinogenesis. We aim to evaluate dietary PE intake and lung cancer risk using data from the Prostate, Lung, Colorectal and Ovarian cancer screening trial. A total of 1706 lung cancer cases were identified. The association between lung cancer risk and PE intake (in quartiles) was calculated using the Cox proportional hazard models adjusting for potential confounders. Stratified analyses by smoking status, sex and histology were also performed. The highest quartile of total PE intake was associated with a reduced risk of lung cancer compared with the lowest quartile [hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.73-0.99 for >1030 μg/day versus <290 μg/day] (P trend = 0.56). Similar patterns were observed among ever smokers (HR = 0.84, 95% CI: 0.71-0.98), non-small cell histology (HR = 0.84, 95% CI: 0.72-0.99), male (HR = 0.84, 95% CI: 0.69-1.03) and female (HR = 0.80, 95% CI: 0.64-0.99 for 510-1030 μg/day, HR = 0.84, 95% CI: 0.67-1.06 for >1030 μg/day versus <290 μg/day) subjects with no significant linear trend observed. Despite a lower consumption compared with the Asian population, increased PE intake still appears to decrease lung cancer risk in a Caucasian-dominant population. Future studies are needed to replicate these results in independent cohorts and shed a light on the potential mechanism of the protective effect of PEs on lung carcinogenesis and the interaction between PEs, smoking and endogenous estrogens.

Topics: Aged; Colorectal Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Ovarian Neoplasms; Phytoestrogens; Proportional Hazards Models; Prostatic Neoplasms; Risk Factors

In this study we aimed to investigate the association between dietary phytoestrogen consumption and prostate cancer in a sample of southern Italian individuals.. A population-based case-control study on the association between prostate cancer and dietary factors was conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy (Registration number: 41/2015). A total of 118 histopathological-verified prostate cancer (PCa) cases and a total of 222 controls were collected. Dietary data was collected by using two food frequency questionnaires.. Patients with PCa consumed significantly higher levels of phytoestrogens. Multivariate logistic regression showed that lignans (Q[quartile]4 vs. Q1, OR [odds ratio] = 4.72; p < .05) and specifically, lariciresinol (Q4 vs. Q1, OR = 4.60; p < .05), pinoresinol (Q4 vs. Q1, OR = 5.62; p < .05), matairesinol (Q4 vs. Q1, OR = 3.63; p < .05), secoisolariciresinol (Q4 vs. Q1, OR = 4.10; p < .05) were associated with increased risk of PCa. Furthermore, we found that isoflavones (Q3 vs. Q1, OR = 0.28; p < .05) and specifically, genistein (Q4 vs. Q1, OR = 0.40; p < .05) were associated with reduced risk of PCa.. We found of an inverse association between dietary isoflavone intake and PCa, while a positive association was found with lignans intake.

Topics: Aged; Case-Control Studies; Diet; Diet Surveys; Genistein; Humans; Lignans; Logistic Models; Male; Middle Aged; Phytoestrogens; Prostate; Prostatic Neoplasms; Risk Factors; Sicily

Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S-phase kinase-associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dihydrotestosterone; Equol; Humans; Male; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Binding; Receptors, Androgen; S-Phase Kinase-Associated Proteins

In prostate cancer, DNA methylation is significantly associated with tumor initiation, progression, and metastasis. Previous studies have suggested that soy phytoestrogens might regulate DNA methylation at individual candidate gene loci and that they play a crucial role as potential therapeutic agents for prostate cancer. The purpose of our study was to examine the modulation effects of phytoestrogens on a genome-wide scale in regards to DNA methylation in prostate cancer. Prostate cancer cell lines DU-145 and LNCaP were treated with 40 μM of genistein and 110 μM of daidzein. DNMT inhibitor 5-azacytidine (2 μM) and the methylating agent budesonide (2 μM) were used to compare their demethylation/methylation effects with phytoestrogens. The regulatory effects of phytoestrogens on DNA methylation were analyzed by using a methyl-DNA immunoprecipitation method coupled with Human DNA Methylation Microarrays (MeDIP-chip). We observed that the methylation profiles of 58 genes were altered by genistein and daidzein treatments in DU-145 and LNCaP prostate cancer cells. In addition, the methylation frequencies of the MAD1L1, TRAF7, KDM4B, and hTERT genes were remarkably modified by genistein treatment. Our results suggest that the modulation effects of phytoestrogens on DNA methylation essentially lead to inhibition of cell growth and induction of apoptosis. Genome-wide methylation profiling reported here suggests that epigenetic regulation mechanisms and, by extension, epigenetics-driven novel therapeutic candidates warrant further consideration in future "omics" studies of prostate cancer.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Azacitidine; Budesonide; Cell Line, Tumor; Cell Proliferation; DNA Methylation; DNA, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genistein; Glycine max; Humans; Isoflavones; Male; Oligonucleotide Array Sequence Analysis; Phytoestrogens; Prostatic Neoplasms

Bisphenol A (BPA) is one hormonally active chemical with potential deleterious effects on reproductive organs, including breast and prostate. In contrast, genistein (GEN) is the major phytoestrogen of soy that presents potential protective effects against hormone-dependent cancers, including that of the prostate. Thus, pregnant Sprague-Dawley rats were treated with BPA at 25 or 250 μg/kg/day by gavage from gestational day (GD) 10-21 with or without dietary GEN at 250 mg/kg/chow (∼5.5 mg/kg/day). Then, male offspring from different litters were euthanized on post-natal day (PND) 21 and 180. At PND21, BPA 25 exposure induced early prostatic changes while dietary GEN attenuated some deleterious actions this xenoestrogen on epithelial cell proliferation levels, androgen receptor expression and prostatic architecture in male offspring. At PND180, a significant increase in incidence of prostatic multifocal inflammation/reactive hyperplasia and atypical hyperplasia were observed in male offspring from dams that received BPA 25. On the other hand, maternal GEN feeding attenuated some the adverse effects of BPA 25 on prostate disease at late-in-life. This way, the present findings point to preventive action of dietary GEN on deleterious effects of gestational BPA exposure in both early and late prostate development in offspring F1.

Topics: Animals; Benzhydryl Compounds; Cell Proliferation; Dietary Supplements; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Genistein; Male; Maternal Nutritional Physiological Phenomena; Phenols; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Rats, Sprague-Dawley; Receptors, Androgen; Specific Pathogen-Free Organisms; Weaning

In Europe, prostate cancer (PC) is the most common malignancy in males. There are three known risk factors strongly coherent to the development of PC: heredity, ethnical origin, and age. Migration studies have shown that environmental factors may influence the development of PC. In this context, specific nutritional components may exert an influence on the tumorigenesis of PC. Primary prevention of PC is still an important issue due to its high prevalence, treatment-associated morbidities, and long-term complications. Phytoestrogenes as flavonoids seem to play an essential role in the chemoprevention of PC which is possibly due to their hormonal function and antioxidative capability. Flavonoids and their subgroups are naturally existent in traditional asian and vegetarian nutrients as coverings of plants, fruits, and vegetables. Two of the most frequently investigated flavonoids are genistein and quercetin. These nutritional components may have therapeutic potential and may impact the development of PC. Even though these flavonoids show promising results in the chemoprevention of PC, the literature is almost experimental, epidemiological, and retrospective with a missing long-term follow-up. Therefore, randomized clinical trials are urgently needed to evaluate in depth its oncologic effects in PC.

Topics: Chemoprevention; Genistein; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Quercetin; Treatment Outcome

Major phytoestrogens genistein and daidzein have been reported to have the ability to reverse DNA methylation in cancer cell lines. The mechanism by which genistein and daidzein have an inhibiting action on DNA methylation is not well understood. The aim of this study was to investigate the effects of soy phytoestrogens and the natural estrogen 17β-estradiol (E2) to determine whether one of the estrogen receptors is mobilized for the action of these compounds on DNA methylation. We also made a comparative study with a DNA methylation inhibitor (5-azacytidine) and a DNA methylation activator (budesonide). Three prostate cell lines, PC-3, DU-145, and LNCaP, were treated with 40 μM genistein, 110 μM daidzein, 2 μM budesonide, 2 μM 5-azacytidine, and 10 μM E2. In these 3 human prostate cancer cell lines, we performed methylation quantification using methyl-profiler-DNA-methylation analysis. Soy phytoestrogens and E2 induced a demethylation of all the promoter regions studied except for those that were unmethylated in control cells. Our results showed that E2 induces, like soy phytoestrogen, a decrease in DNA methylation in prostate cancer cell lines. This action may be mediated through ERβ.

Topics: Azacitidine; Budesonide; Cell Line, Tumor; DNA Methylation; Estradiol; Estrogen Receptor beta; Gene Expression Regulation, Neoplastic; Genistein; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Promoter Regions, Genetic; Prostatic Neoplasms

Prostate cancer is one of the most prevalent malignant cancers in men. The isoflavone formononetin is a main active component of red clover plants. In the present study, we assessed the effect of formononetin on human prostate cancer DU-145 cells in vitro, and elucidated possible mechanisms. DU-145 cells were treated with different concentrations of formononetin and cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 and flow cytometry, and protein levels of RASD1, Bcl-2 and Bax by Western blotting. The results showed that formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax. The level of RASD1 reached its maximum at 48 h post-treatment, and rapidly decreased thereafter. Together, we present evidence that formononetin triggered cell apoptosis through the mitochondrial apoptotic pathway by up-regulating RASD1.

Topics: Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cell Proliferation; Flow Cytometry; Humans; In Vitro Techniques; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; ras Proteins; Tumor Cells, Cultured

Topics: Breast Neoplasms, Male; Carcinoma, Ductal, Breast; Carcinoma, Papillary; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Phytoestrogens; Prognosis; Prostatic Neoplasms

In the present study, the main natural estrogen-agonist/antagonist from Pigeonpea roots was studied by the estrogen receptor α-dependent signaling pathway in human prostate cancer cell. First, the natural products with estrogenic activity in Pigeonpea roots were screened by pER8-GFP transgenic Arabidopsis, and cajanol (5-hydroxy-3-(4-hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one) was confirmed as the active compound. Further study showed that cajanol significantly arrested the cell cycle in the G1 and G2/M phase and induced nuclei condensation, fragmentation and the formation of apoptotic bodies. Western blotting showed that cajanol modulated the ERα-dependent PI3K pathway and induced the activation of GSK3 and CyclinD1 closely following the profile of PI3K activity. Based on above results, we proposed a mechanism through which cajanol could inhibit survival and proliferation of estrogen-responsive cells (PC-3 cells) by interfering with an ERα-associated PI3K pathway, following a process that could be dependent of the nuclear functions of the ERα. Above all, we conclude that cajanol represents a valuable natural phytoestrogen source and may potentially be applicable in health food industry.

Topics: Arabidopsis; Cajanus; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin D1; Estrogen Receptor alpha; Glycogen Synthase Kinase 3; Humans; Isoflavones; Male; Phosphatidylinositol 3-Kinases; Phytoestrogens; Plant Roots; Plants, Genetically Modified; Prostatic Neoplasms; Signal Transduction

Some clinical trials have shown that high phytoestrogen intake may decrease serum concentrations of prostate-specific antigen (PSA), and phytoestrogens may also lower prostate cancer risk. It was the aim of this study to examine the relationship between the serum PSA level and urine phytoestrogen concentration in generally healthy U.S. men. Eight hundred twenty-four men, 40+ yr old without prostate cancer, who participated in the 2001-2004 NHANES surveys, were included in the analysis. The association of total PSA, free PSA, and PSA ratio [free PSA/total PSA * 100] with concentrations of isoflavones and lignans (standardized for urinary creatinine concentration) was examined using multivariable-adjusted linear and logistic regression models. The linear regression analyses showed no clear association between creatinine-standardized urinary phytoestrogen concentrations and serum total or free PSA levels or PSA ratio. However, the odds of having a PSA ratio <15% rose from Quartile 1 to Quartile 4 of isoflavone excretion (odds ratio = 2.82, 95% confidence interval 1.28-6.22 for top vs. bottom quartile), but there were no associations with having a PSA ratio <25%. In generally healthy U.S. men, 40+ yr old without a diagnosis of prostate cancer, urinary isoflavone, and lignan concentrations were not associated with serum PSA level.

Topics: Adult; Body Mass Index; Creatinine; Cross-Sectional Studies; Humans; Isoflavones; Lignans; Linear Models; Logistic Models; Male; Middle Aged; Motor Activity; Multivariate Analysis; Nutrition Surveys; Odds Ratio; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Socioeconomic Factors

Intake of dietary phyto-oestrogens has received a great deal of attention owing to their potential influence on hormone-sensitive cancers such as breast and prostate cancer. Cows' milk contains phyto-oestrogens and the content varies according to the composition of the feed and the type and amount of legumes used. In this study we evaluated the proliferative effect of milk (whey) with different phyto-oestrogen content in human breast (MCF-7) and prostate cancer cells (PC-3). Milk was obtained from cows fed either a birdsfoot trefoil-timothy silage based ration (B1) or two different red clover silage based diets (R1 and R2) resulting in total phyto-oestrogen contents of 403, 1659 and 1434 ng/ml for the B1, R1 and R2 diets, respectively. Whey was produced from the milk and added to cell culture medium in concentrations up to 10% for MCF-7 cells and 5% for PC-3 cells. Cell proliferation was measured fluorometrically after 7 d for MCF-7 cells and 5 d for PC-3 cells. There was no significant difference in the proliferative effect of whey from the different dietary treatments at any of the whey concentrations tested. An anti-proliferative effect (P<0·01) of 5 and 10% whey was seen when tested in the presence of 10 pM oestradiol in the medium. This effect was independent of dietary treatment of cows. Whey induced a significant (P<0·01) proliferative response in PC-3 cells independent of dietary treatment. Purified equol in concentrations similar to equol concentrations in milk decreased PC-3 cell proliferation, and therefore the stimulatory effect of whey in PC-3 cells is believed to be mediated by other bioactives than equol. In conclusion, our results suggest that using whey in these proliferation assays, it was not possible to discriminate between milk with high or low levels of phyto-oestrogens.

Topics: Animal Feed; Animals; Breast Neoplasms; Cattle; Cell Line, Tumor; Cell Proliferation; Fabaceae; Female; Humans; Lotus; Male; Milk; Phleum; Phytoestrogens; Prostatic Neoplasms; Silage; Trifolium

Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERβ, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERβ is anti-proliferative. Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers. Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/β heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/β heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays, we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Growth Inhibitors; Humans; Ligands; Male; Phytoestrogens; Prostatic Neoplasms; Protein Multimerization; Receptors, Estrogen

AdΔΔ is an oncolytic adenoviral mutant that has been engineered to selectively target tumors with deregulated cell cycle and apoptosis pathways. AdΔΔ potentiates apoptotic cell death induced by drugs, including mitoxantrone and docetaxel, which are commonly used to treat prostate cancer. Here, we demonstrate that AdΔΔ can also interact synergistically with dietary phytochemicals known to have anti-cancer activities, without incurring the toxic side effects of chemodrugs. Curcumin, genistein, epigallocatechin-gallate, equol, and resveratrol efficiently killed both androgen-receptor positive (22Rv1) and negative cell lines (PC-3, DU145) in combination with adenoviral mutants. Synergistic cell killing was demonstrated with wild-type virus (Ad5) and AdΔΔ in combination with equol and resveratrol. EC(50) values for both phytochemicals and viruses were reduced three- to eightfold in all three combination-treated cell lines. The most potent efficacy was achieved in the cytotoxic drug- and virus-insensitive PC-3 cells, both in vitro and in vivo, while cell killing in normal bronchial epithelial cells was not enhanced. Although equol and resveratrol induced only low levels of apoptosis when administered alone, in combination with wild-type virus or AdΔΔ, the level of apoptotic cell death was significantly increased in PC-3 and DU145 cells. In vivo studies using suboptimal doses of AdΔΔ and equol or resveratrol, showed reduced tumor growth without toxicity to normal tissue. These findings identify novel functions for AdΔΔ and phytochemicals in promoting cancer cell killing and apoptosis, suggesting the use of these natural nontoxic compounds might be a feasible and currently unexploited anti-cancer strategy.

Topics: Adenoviridae; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Dietary Supplements; Equol; Humans; Male; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Oncolytic Viruses; Phytoestrogens; Prostatic Neoplasms; Resveratrol; Stilbenes; Transplantation, Heterologous

Combination of dietary phytoestrogens with diverse molecular mechanisms may enhance their anticancer efficacy at physiological concentrations, as evidenced in epidemiological studies. A select combination of three dietary phytoestrogens containing 8.33 μM each of genistein (G), quercetin (Q) and biochanin A (B) was found to be more potent in inhibiting the growth of androgen-responsive prostate cancer cells (LNCaP) as well as DU-145 and PC-3 prostate cancer cells in vitro than either 25 μM of G, B or Q or 12.5+12.5 μM of G+Q, Q+B or G+B. Subsequent mechanistic studies in PC-3 cells indicated that the action of phytoestrogens was mediated both through estrogen receptor (ER)-dependent and ER-independent pathways as potent estrogen antagonist ICI-182780 (ICI, 5 μM) could not completely mask the synergistic anticancer effects, which were sustained appreciably in presence of ICI. G+Q+B combination was significantly more effective than individual compounds or their double combinations in increasing ER-β, bax (mRNA expression); phospho-JNK, bax (protein levels); and in decreasing bcl-2, cyclin E, c-myc (mRNA expression); phospho-AKT, phospho-ERK, bcl-2, proliferating cell nuclear antigen (protein levels) in PC-3 cells. Phytoestrogens also synergistically stimulated caspase-3 activity. Our findings suggest that selectively combining anticancer phytoestrogens could significantly increase the efficacy of individual components resulting in improved efficacy at physiologically achievable concentrations. The combination mechanism of multiple anticancer phytochemicals may be indicative of the potential of some vegetarian diet components to elicit chemopreventive effects against prostate cancer at their physiologically achievable concentrations, in vivo.

Topics: bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Cyclin E; Diet; Down-Regulation; Drug Synergism; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Fulvestrant; Genistein; Humans; Male; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phytoestrogens; Prostatic Neoplasms; Quercetin; Signal Transduction; Up-Regulation

To compare the effect of R- and S-enantiomers of equol on the motility and invasion in human prostate cancer cells PC3 and DU145.. Wound healing assay and transwell invasion assay were performed to assess the cell motility and invasion. Gelatin zymography and RT-PCR assay were performed to assess the related protein activity and mRNA expression.. R-(+) equol and S-(-)equol inhibited motility and invasion in PC3 and DU145 cells, separately. The results were more obvious in PC3 cells, and effect of R-(+) equol was stronger than its enantiomer S-(-) equol. MMP-2, MMP-9, the crucial members in metastasis, were found down-regulated by R-(+)equol and S-(-)equol. Subsequently, the estrogen receptor-alpha was activated by R-(+) equol, while no such effect on estrogen receptor-beta was observed.. R-(+) equol and S-(-) equol inhibited motility and invasion in PC3 and DU145 cells, while the most strong effect was observed in PC3 cells by R-(+) equol, which might regulated by the activation of estrogen receptor-alpha.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Equol; Humans; Male; Neoplasm Invasiveness; Phytoestrogens; Prostatic Neoplasms; Stereoisomerism

DNA hypermethylation is an epigenetic mechanism which induces silencing of tumor-suppressor genes in prostate cancer. Many studies have reported that specific components of food plants like soy phytoestrogens may have protective effects against prostate carcinogenesis or progression. Genistein and daidzein, the major phytoestrogens, have been reported to have the ability to reverse DNA hypermethylation in cancer cell lines. The aim of this study was to investigate the potential demethylating effects of these two soy compounds on BRCA1, GSTP1, EPHB2 and BRCA2 promoter genes.. Prostate cell lines DU-145 and PC-3 were treated with genistein 40 µM, daidzein 110 µM, budesonide (methylating agent) 2 µM and 5-azacytidine (demethylating agent) 2 µM. In these two human prostate cancer cell lines we performed methylation quantification by using Methyl Profiler DNA methylation analysis. This technique is based on a methylation-specific digestion followed by quantitative PCR. We analyzed the corresponding protein expression by western blotting.. Soy phytoestrogens induced a demethylation of all promoter regions studied except for BRCA2, which is not methylated in control cell lines. An increase in their protein expression was also demonstrated by western blot analysis and corroborated the potential demethylating effect of soy phytoestrogens.. This study showed that the soy phytoestrogens, genistein and daidzein, induce a decrease of methylation of BRCA1, GSTP1 and EPHB2 promoters. Therefore, soy phytoestrogens may have a protective effect on prostate cancer. However, more studies are needed in order to understand the mechanism by which genistein and daidzein have an inhibiting action on DNA methylation.

Topics: Blotting, Western; BRCA1 Protein; BRCA2 Protein; Cell Line, Tumor; DNA Methylation; Flow Cytometry; Genes, Tumor Suppressor; Genistein; Glutathione S-Transferase pi; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Promoter Regions, Genetic; Prostatic Neoplasms; Receptor, EphB2

The characterization of phytoestrogen intake and cancer risk has been hindered by the absence of accurate dietary phytoestrogen values.. We examined the risk of breast, colorectal, and prostate cancers relative to phytoestrogen intake on the basis of a comprehensive database.. Demographic and anthropometric characteristics, a medical history, and 7-d records of diet were collected prospectively from participants (aged 40-79 y) in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Five hundred nine food items were analyzed by liquid chromatography-mass spectrometry/mass spectrometry, and (13)C(3)-labeled internal standards were analyzed for isoflavones (genistein, daidzein, glycitein, biochanin A, and formononetin), lignans (secoisolariciresinol and matairesinol), and enterolignans from gut microbial metabolism in animal food sources (equol and enterolactone). From the direct analysis, values for 10,708 foods were calculated. Odds ratios (ORs) for breast (244 cases, 941 controls), colorectal (221 cases, 886 controls), and prostate (204 cases, 812 controls) cancers were calculated relative to phytoestrogen intake.. Phytoestrogen intake was not associated with breast cancer among women or colorectal cancer among men. Among women, colorectal cancer risk was inversely associated with enterolactone (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for secoisolariciresinol (OR: 1.60; 95% CI: 0.96, 2.69). A positive trend between enterolignan intake and prostate cancer risk (OR: 1.27; 95% CI: 0.97, 1.66) was attenuated after adjustment for dairy intake (OR: 1.19; 95% CI: 0.77, 1.82).. Dietary phytoestrogens may contribute to the risk of colorectal cancer among women and prostate cancer among men.

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Gas Chromatography-Mass Spectrometry; Humans; Incidence; Isoflavones; Lignans; Logistic Models; Male; Middle Aged; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Risk Factors; Spectrometry, Mass, Electrospray Ionization; United Kingdom

Previous studies have suggested that soy isoflavones exert anticarcinogenic effects against prostate cancer. We propose that soy extracts, containing a mixture of soy isoflavones and other bioactive components, would be a more potent chemo-preventive agent than individual soy isoflavones. We compared the apoptotic effects of whole soy extracts and individual soy isoflavones, genistein and daidzein, on prostate cancer cells. The soy extract contained 50% w/w of total isoflavones with approximately 1:5.5:3.5 ratios of genistin, daidzin and glycitin, respectively. Benign prostate hyperplasia (BPH-1), LnCap and PC3 cells were treated with varying concentrations of soy extract, genistein or daidzein and analyzed for cell cycle alterations and induction of apoptosis. At equal concentrations (25 micromol/L), soy extract induced a significantly higher percentage of cells undergoing apoptosis than genistein or daidzein (P < 0.001). No significant changes in cell cycle arrest or apoptosis were observed in non-cancerous BPH-1 cells treated with soy extract, suggesting that the effects of soy extract may be tumor cell specific. On the contrary, both genistein and daidzein induced apoptosis in BPH-1 cells, suggesting that individual isoflavones may have cytotoxicity in non-cancerous cells. Soy extracts also increased Bax expression in PC3 cells, but no significant changes in nuclear factor kappaB (NF kappaB) activation were detected, suggesting that the induction of apoptosis was independent of the NF kappaB pathway. Food products that bear a combination of active compounds may be more efficacious and safer as chemo-preventive agents than individual compounds. This 'whole-food'-based approach is significant for the development of public health recommendations for prostate cancer prevention.

Topics: Anticarcinogenic Agents; Apoptosis; bcl-2-Associated X Protein; Caspases; Cell Cycle; Cell Line, Tumor; Dietary Supplements; Enzyme Activation; Glycine max; Humans; Isoflavones; Male; NF-kappa B; Phytoestrogens; Plant Extracts; Prostatic Neoplasms

We evaluated the relationship of spot urinary concentrations of phytoestrogens with total prostate cancer and tumor grade in a hospital-based case-control study in Jamaica. Urine samples were analyzed for genistein, daidzein, equol (isoflavones), and enterolactone (lignan) among newly diagnosed cases (n = 175) and controls (n = 194). Urinary concentrations of enterolactone (lignan) were higher among cases. There were no significant differences in median concentrations of isoflavone excretion. Compared with non-producers of equol (reference tertile), men who produced equol were at decreased risk of total prostate cancer (tertile 2: OR, 0.42; CI, 0.23-0.75) (tertile 3: OR, 0.48; CI, 0.26-0.87) (p (trend), 0.020) and high-grade disease (tertile 2: OR, 0.31; CI, 0.15-0.61) (tertile 3: OR, 0.29; CI, 0.13-0.60) (p (trend), 0.001). Higher concentrations of enterolactone were positively related to total prostate cancer (OR, 1.85; CI, 1.01-3.44; p (trend), 0.027) as well as high-grade disease (OR, 2.46; CI, 1.11-5.46; p (trend), 0.023). There were no associations between urinary excretion of genistein and daidzein with risk of prostate cancer. Producers of equol (isoflavone) may be at reduced risk of total- and high-grade prostate cancer whereas enterolactone may increase the likelihood of disease.

Topics: Aged; Carcinoma; Case-Control Studies; Equol; Genistein; Humans; Isoflavones; Jamaica; Lignans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk

We examined plasma concentrations of phyto-oestrogens in relation to risk for subsequent prostate cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. Concentrations of isoflavones genistein, daidzein and equol, and that of lignans enterolactone and enterodiol, were measured in plasma samples for 950 prostate cancer cases and 1042 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of these phyto-oestrogens were estimated by conditional logistic regression. Higher plasma concentrations of genistein were associated with lower risk of prostate cancer: RR among men in the highest vs the lowest fifth, 0.71 (95% confidence interval (CI) 0.53-0.96, P trend=0.03). After adjustment for potential confounders this RR was 0.74 (95% CI 0.54-1.00, P trend=0.05). No statistically significant associations were observed for circulating concentrations of daidzein, equol, enterolactone or enterodiol in relation to overall risk for prostate cancer. There was no evidence of heterogeneity in these results by age at blood collection or country of recruitment, nor by cancer stage or grade. These results suggest that higher concentrations of circulating genistein may reduce the risk of prostate cancer but do not support an association with plasma lignans.

Topics: Case-Control Studies; Diet; Europe; Genistein; Humans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Factors

Phytoestrogens are of special interest in prostate cancer research because populations in Asia with a high consumption of phytoestrogens have a lower incidence of the disease than comparable populations in Western countries.. This case-control study is nested within a large multiethnic cohort in Hawaii and California. Urine samples were analysed for daidzein, genistein, equol, and enterolactone among 249 incident prostate cancer cases and 404 controls matched on age, race/ethnicity, date/time of specimen collection, and fasting status.. The median excretion of daidzein was 0.173 nmol mg(-1) creatinine in cases and 0.291 in controls (P=0.01), and the median excretion of genistein was 0.048 in cases and 0.078 in controls (P=0.05). An inverse association was seen for daidzein overall (odds ratio for the highest vs lowest quintile=0.55, 95% confidence interval=0.31-0.98, P(trend)=0.03) and seemed to apply to localized (P(trend)=0.08) as well as advanced or high-grade cancer (P(trend)=0.09). This association was consistent across the four ethnic groups examined. Although the relationship was weaker for genistein, the odds ratios and trends were similarly inverse. Urinary excretion of equol and enterolactone was not significantly related to prostate cancer risk.. Our findings suggest that high intake of isoflavones, as reflected by urinary excretion of daidzein and genistein, may be protective against prostate cancer.

Topics: Aged; California; Case-Control Studies; Cohort Studies; Genistein; Hawaii; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms

Prostate cancer (PCa) has a high propensity to metastasize to the bone. PCa cells produce several bone-related factors, namely parathyroid hormone related protein (PTHrP), its PTH type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of NF-kappa B ligand (RANKL). The effects of these factors might explain, at least in part, the ability of PCa cells to grow in and interact with bone.. We first analyzed the expression of the aforementioned factors (by western blot and flow cytometry), and their modulation by the phytoestrogens genistein and daidzein (as potential anti-tumoral agents), in human PCa cells in vitro. We also assessed the impact of these osteomimetic factors on PCa cell viability (by propidium iodide staining and flow cytometry, and trypan blue staining).. Genistein and daidzein, at nM range, increased both the PTHrP/PTH1R system and the OPG/RANKL protein ratio, while genistein and, to a lesser extent, daidzein, at >microM doses, inhibited cell viability in PCa cells. Both N- and C-terminal domains of PTHrP inhibited genistein-induced cell death by modulating transcription factor Runx-2 and the Bcl-2/Bax protein ratio in PCa cells.. Our findings indicate that high doses of genistein and daidzein cause PCa cell death. On the other hand, low doses of these phytoestrogens induce some osteomimetic features in PCa cells with putative impact on PCa development.

Topics: Blotting, Western; Bone and Bones; Cell Death; Cell Line, Tumor; Cell Survival; Cytokines; Flow Cytometry; Genistein; Humans; Isoflavones; Male; Osteoprotegerin; Parathyroid Hormone-Related Protein; Phytoestrogens; Prostatic Neoplasms; RANK Ligand; Receptor, Parathyroid Hormone, Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Transfection

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors alpha (ESR1) and beta (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3' of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3' of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.

Topics: Aged; Body Mass Index; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genetic Predisposition to Disease; Genotype; Humans; Logistic Models; Male; Middle Aged; Phytoestrogens; Polymorphism, Single Nucleotide; Prostatic Neoplasms

To create physician awareness of complementary and alternative medicine therapy use in patients with prostate cancer so that physicians can monitor for adverse events. Approximately one fourth to one third of patients diagnosed with prostate cancer reported complementary and alternative medicine use, and many of these patients are taking a supplement called "Dr. Donsbach's Prostasol.". We discuss the cases of 2 patients with prostate cancer who were taking Dr. Donsbach's Prostasol and developed venous thromboembolic events while taking this supplement, in the absence of other obvious risk factors. We review these 2 cases and the time-line for the development of the venous thromboembolic events and use of Dr. Donsbach's Prostasol. We compared Prostasol with PC-SPES, a similar supplement that was associated with thrombosis and was ultimately taken off the market because of patient safety concerns.. Prostasol contains phytoestrogens that could result in both the suppression of testosterone and the predisposition to thrombosis. Both patients had suppression of their testosterone to castrate levels with an associated decrease in prostate-specific antigen at the time of their thrombotic event.. These cases are suggestive of an association between Prostasol use and venous thromboembolic events. Physicians should be aware of the use of this agent in their patients, although it is not known whether it would be appropriate to prescribe prophylactic low-dose warfarin therapy. If possible, additional study of complementary and alternative medicine therapies for safety and efficacy are indicated.

Topics: Aged; Aged, 80 and over; Complementary Therapies; Dietary Supplements; Drugs, Chinese Herbal; Enoxaparin; Humans; Male; Medical Oncology; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Venous Thromboembolism; Venous Thrombosis; Warfarin

Dietary phytoestrogens are suggested to reduce the risk of prostate and colorectal cancer, but the results of epidemiologic studies have not yielded consistent support for this proposed effect, possibly due to inadequate databases of phytoestrogen levels in foods. Biomarkers of phytoestrogen intakes may provide a clearer insight into the relationship between phytoestrogen exposure and the risk of prostate or colorectal cancer risks. From the European Prospective into Cancer-Norfolk cohort (ages 45-75), serum and urine samples were analyzed for seven phytoestrogens [daidzein, enterodiol, enterolactone, genistein, glycitein, O-desmethylangolensin (O-DMA), and equol] among 193 cases of prostate cancer and 828 controls, and 221 cases of colorectal cancer with 889 controls. Summary variables of total lignans (enterodiol and enterolactone) and total isoflavones (daidzein, genistein, O-DMA, equol, and glycitein) were created and analyzed in conjunction with individual phytoestrogens. Logistic regression analyses revealed that there was no significant association between prostate cancer risk and total serum isoflavones [odds ratio (OR), 1.01; 95% confidence interval (CI), 0.93-1.10] or total serum lignans (OR, 0.94; 95% CI, 0.86-1.04) or between colorectal cancer risk and total serum isoflavones (OR, 1.01; 95% CI, 0.94-1.08) or total serum lignans (OR, 1.03; 95% CI, 0.94-1.12). Similarly, null associations were observed for individual serum phytoestrogens and for all urinary phytoestrogen biomarkers. In conclusion, we have found no evidence to support an inverse association between phytoestrogen exposure and prostate or colorectal cancer risk.

Topics: Aged; Case-Control Studies; Colorectal Neoplasms; England; Female; Humans; Logistic Models; Male; Middle Aged; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Registries; Risk

Ecological data suggest a long-term diet high in plant material rich in biologically active compounds, such as the lignans, can significantly influence the development of prostate cancer over the lifetime of an individual. The capacity of a pure mammalian lignan, enterolactone (ENL), to influence the proliferation of the LNCaP human prostate cancer cell line was investigated as a function of cell density, metabolic activity, expression and secretion of prostate specific antigen (PSA), cell cycle profile, and the expression of genes involved in development and progression of prostate cancer. Treatment with a subcytotoxic concentration of ENL (60 muM for 72 h) was found to reduce: cell density (57.5%, SD 7.23, p < 0.001), metabolic activity (55%, SD 0.03, p < 0.001), secretion of PSA (48.50% SD 4.74, p = 0.05) and induce apoptosis (8.33-fold SD 0.04, p = 0.001) compared to untreated cells. Cotreatment with 10 muM etoposide was found to increase apoptosis by 50.17% (SD 0.02, p < 0.001). Additionally, several key genes (e. g. MCMs, survivin and CDKs) were beneficially regulated by ENL treatment (p < 0.05). The data suggest that the antiproliferative activity of ENL is a consequence of altered expression of cell cycle associated genes and provides novel molecular evidence for the antiproliferative properties of a pure lignan in prostate cancer.

Topics: 4-Butyrolactone; Cell Division; Cell Line, Tumor; Cell Survival; Humans; Lignans; Male; Mitochondria; Phytoestrogens; Polymerase Chain Reaction; Prostate-Specific Antigen; Prostatic Neoplasms

Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappaB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer.

Topics: Acetylation; Anticarcinogenic Agents; Antimetabolites, Antineoplastic; Azacitidine; Blotting, Western; Cell Line, Tumor; Chromatin Immunoprecipitation; Chromones; CpG Islands; Decitabine; Deubiquitinating Enzyme CYLD; Down-Regulation; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, Tumor Suppressor; Genistein; Histones; Humans; Hydroxamic Acids; Male; Methylation; Morpholines; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phytoestrogens; Prostatic Neoplasms; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Sirtuins; Tumor Suppressor Proteins; Up-Regulation

To identify the phytoandrogen from phytohormone, we established an assay to assess the androgenicity of phytoestrogens by using androgen receptor (AR) cofactors to modulate the AR transcriptional activity.. A Dual-luciferase reporter assay was used to evaluate the transcriptional activity of AR stimulated by the phytoestrogen daidzein.. The Dual luciferase data showed that daidzein can enhance androgenic effects in AR negative PC-3 cells cotransfected with AR and AR cofactors. In AR and ARA70 positive LNCaP cells, daidzein can enhance ARA55-mediated induction of AR transcriptional activity. With increasing amounts of transfected ARA55, AR transcriptional activity was enhanced by daidzein in a dose-dependent manner.. Although daidzein is a phytoestrogen, it can create androgenic effects when cells are cotransfected with AR cofactors. When screening for phytoandrogens, the modulating effects of AR cofactors with AR should be considered in the assay system.

Topics: Cell Line, Tumor; Dihydrotestosterone; Estradiol; Humans; Intracellular Signaling Peptides and Proteins; Isoflavones; LIM Domain Proteins; Male; Nuclear Receptor Coactivators; Oncogene Proteins; Phytoestrogens; Prostatic Neoplasms; Receptors, Androgen; Transcription Factors; Transcription, Genetic; Transfection

A population-based case-control study of diet, inherited susceptibility and prostate cancer was undertaken in the lowlands and central belt of Scotland to investigate the effect of phyto-oestrogen intake and serum concentrations on prostate cancer risk. A total of 433 cases and 483 controls aged 50-74 years were asked to complete a validated FFQ and provide a non-fasting blood sample. Multivariate logistic regression analysis found significant inverse associations with increased serum concentrations of enterolactone (adjusted OR 0.40, 95 % CI 0.22, 0.71] and with the consumption of soy foods (adjusted OR 0.52, 95 % CI 0.30, 0.91). However, no significant associations were observed for isoflavone intake or serum genistein, daidzein and equol. This study supports the hypotheses that soy foods and enterolactone metabolised from dietary lignans protect against prostate cancer in older Scottish men.

Topics: 4-Butyrolactone; Aged; Case-Control Studies; Diet; Diet Surveys; Energy Intake; Equol; Genistein; Humans; Isoflavones; Lignans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Assessment; Scotland

To investigate the changes in expression underlying the marked reduction of tumour growth in vivo, by analysing the effect of Belamcanda chinensis extract (BCE) on LNCaP cells in vitro, as phytoestrogens are chemopreventive in prostate cancer, and in previous studies we examined the effects of the isoflavone tectorigenin isolated from B. chinensis on LNCaP prostate cancer cells, and a BCE consisting of 13 phytoestrogenic compounds on tumour-bearing nude mice.. LNCaP cells were treated with 100, 400 or 1400 microg/mL BCE; proliferation was assessed with an Alamar Blue assay. We used real-time reverse transcription-polymerase chain reaction to quantify mRNA expression of the androgen receptor (AR), the AR coactivator prostate derived Ets transcription factor (PDEF), NKX3.1, prostate specific antigen (PSA) and oestrogen receptor-beta (ER-beta) compared with the expression of the housekeeping gene porphobilinogen deaminase (PBGD). PSA secretion from LNCaP cells was measured and protein expression of the AR investigated by Western blot analysis.. Concomitant with a marked decrease of tumour cell proliferation BCE down-regulated the expression of the AR, PDEF, NKX3.1 and PSA. In the same experiments, the expression of PBGD was unaltered, whereas ER-beta expression increased. Furthermore, AR protein and PSA secretion were markedly diminished after treatments with the BCE.. BCE, comprising 13 different phytoestrogens, decreases the expression of the AR and its co-activator PDEF concomitant with diminished cell proliferation and PSA secretion. NKX3.1 expression was also reduced by BCE. We hypothesise that the positive effects of BCE are initiated by up-regulation of the ER-beta, a putative tumour-suppressor gene.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Humans; Iridaceae; Male; Mice; Mice, Nude; Phytoestrogens; Plant Extracts; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Prostate cancer is more frequently diagnosed in men from Western countries than from Asian societies. Therefore, nutritional factors such as phyto-oestrogens from soya are considered to cause this prostate cancer prevention effect. As there is no curative therapy for hormone-refractory prostate cancer, new strategies are in demand which might include phyto-oestrogens or inhibitors of histone deacetylases. Both approaches have in common the potential to reduce the aberrant androgen receptor and IGF receptor signalling. Furthermore, invasiveness and acquired survival strategies of tumours can be diminished. Reduced tumour cell proliferation and PSA secretion coincide with altered gene expression in the aforementioned processes. In addition, selective knock-down of genes by RNA interference afforded functional analyses regarding impact and succession of expression events involved in the beneficial effects caused by phyto-oestrogens and histone deacetylase inhibitors.

Topics: Biomarkers, Tumor; Cell Division; Complementary Therapies; Gene Expression; Histone Deacetylase Inhibitors; Humans; Male; Phytoestrogens; Phytotherapy; Prostatic Neoplasms; Receptors, Androgen; RNA, Small Interfering; Signal Transduction

Topics: Anticarcinogenic Agents; Equol; Feeding Behavior; Genistein; Humans; Intestines; Isoflavones; Japan; Male; Phytoestrogens; Prostatic Neoplasms; Soy Foods

The mammalian lignan enterolactone is a major metabolite of plant-based lignans that has been shown to inhibit the growth and development of prostate cancer. However, little is known about the mechanistic basis for its anticancer activity. In this study, we report that enterolactone selectively suppresses the growth of LNCaP prostate cancer cells by triggering apoptosis. Mechanistic studies showed that enterolactone-induced apoptosis was characterized by a dose-dependent loss of mitochondrial membrane potential, release of cytochrome c and cleavage of procaspase-3 and poly(ADP-ribose)-polymerase (PARP). Caspase dependence was indicated by the ability of the pan-caspase inhibitor z-VAD-fmk to attenuate enterolactone-mediated apoptosis. Mechanistic studies suggested roles for Akt, GSK-3beta, MDM2, and p53 in enterolactone-dependent apoptosis. Our findings encourage further studies of enterolactone as a promising chemopreventive agent against prostate cancer.

Topics: 4-Butyrolactone; Apoptosis; Caspases; Cell Survival; Cytochromes c; Enzyme Activation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Immunoblotting; In Situ Nick-End Labeling; Lignans; Male; Membrane Potential, Mitochondrial; Mitochondria; Phytoestrogens; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; Tumor Cells, Cultured; Tumor Suppressor Protein p53

In the prostate, estrogen receptor beta (ERbeta), the preferred receptor for phytoestrogens, has features of a tumor suppressor. To investigate the mechanisms underlying the beneficial effects on prostate cancer of histone deacetylase inhibitor valproic acid (VPA) and phytoestrogen tectorigenin, we analyzed the expression of ERbeta after tectorigenin or VPA treatment. For further functional analysis, we knocked down ERbeta expression by RNA interference. LNCaP prostate cancer cells were treated with 5 mmol/L VPA or 100 micromol/L tectorigenin and transfected with small interfering RNA (siRNA) against ERbeta. Control transfections were done with luciferase (LUC) siRNA. Expression of ERbeta was assessed by Western blot. mRNA expression was quantitated by real-time reverse transcription-PCR. Expression of ERbeta mRNA and protein markedly increased after VPA or tectorigenin treatment. When ERbeta was knocked down by siRNA, the expression of prostate-derived Ets factor, prostate-specific antigen, prostate cancer-specific indicator gene DD3(PCA3), insulin-like growth factor-1 receptor, the catalytic subunit of the telomerase, and ERalpha was up-regulated and the tectorigenin effects were abrogated. ERbeta levels were diminished in prostate cancer and loss of ERbeta was associated with proliferation. Here, we show that siRNA-mediated knockdown of ERbeta increases the expression of genes highly relevant to tumor cell proliferation. In addition, we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERbeta resulting in antiproliferative effects. Thus, these drugs, by restoring the regulatory function of ERbeta in tumor cells, could become useful in the intervention of prostate cancer.

Topics: Blotting, Western; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Estrogen Receptor beta; Histone Deacetylase Inhibitors; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tumor Cells, Cultured; Valproic Acid

Phytoestrogenes are plant-derived compounds that have been shown to exert an antiproliferative potential on prostate cancer cells, although the exact mechanisms are still unclear. In prostate cancer cells proliferation is regulated by modulation of the IGF-1 receptor (IGF-R-1) by the androgen receptor (AR) and its co-activator prostate derived Ets factor (PDEF). Phytooestrogenes interact with these mechanisms as demonstrated exemplarily in the presented study with the isoflavone tectorigenin derived from Belamcanda chinensis.. Cultured androgen-sensitive LNCaP prostate cancer cells were treated with tectorigenin of 100 microM for 24 hours. The mRNA-expression of AR, PSA, PDEF, hTERT, TIMP-3 and IGF-R-1 were quantified by real-time RT-PCR. Furthermore, the expression or activity of PSA, telomerase and IGF-R-1 was measured on the protein level. In addition, we investigated in nude mice the influence of a diet of extracts of Belamcanda chinensis on the growth of subcutaneously injected LNCaP cells versus a control group of animals fed with a soy-free diet.. In cultured LNCaP cells treatment with tectorigenin resulted in a significant down-regulation of the gene expression of AR, PDEF, PSA, IGF-R-1 and hTERT. On the protein level PSA secretion and the activity of telomerase and IGF-R-1 expression was also decreased. The gene expression of TIMP-3 was distinctly up-regulated by tectorigenin. Nude mice fed with Belamcanda chinensis extract showed a significantly decreased incidence and tumor growth compared to controls.. Tectorigenin shows an inhibition of the IGF-1-R modulated cell proliferation of PCa-Cells, due to modulation of the activity the co-activator PDEF independently from the AR. Furthermore, tectorigenin has pro-apoptotic effects and decreases tissue invasion by up-regulation of TIMP-3. Therefore, phytooestrogenes are an interesting option in the therapy of prostate especially advanced prostate cancer.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cell Survival; Feasibility Studies; Humans; Isoflavones; Male; Mice; Mice, Nude; Neoplasm Proteins; Phytoestrogens; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Treatment Outcome

High consumption of soy isoflavones in Asian diets has been correlated with a lower incidence of clinically important cases of prostate cancer. The chemopreventive properties of these diets may result from an interaction of several types of isoflavones, including genistein and daidzein. The present study investigated the effects of a soy isoflavone concentrate (ISF) on growth and gene expression profiles of PC-3 human prostate cancer cells. Trypan blue exclusion and [3H]-thymidine incorporation assays showed that ISF decreased cell viability and caused a dose-dependent inhibition of DNA synthesis, respectively, with 50% inhibition (IC50) of DNA synthesis at 52 mg/L (P = 0.05). The glucoside conjugates of genistein and daidzein in ISF were converted to bioactive free aglycones in cell culture in association with the inhibition of DNA synthesis. Flow cytometry and Western immunoblot analyses showed that ISF at 200 mg/L caused an accumulation of cells in the G2/M phase of the cell cycle (P < 0.05) and decreased cyclin A by 20% (P < 0.05), respectively. The effect of ISF on the gene expression profile of PC-3 cells was analyzed using Affymetrix oligonucleotide DNA microarrays that interrogate approximately 17,000 human genes. Of the 75 genes altered by ISF, 28 were upregulated and 47 were downregulated (P < 0.05). Further analysis showed that IL-8, matrix metalloproteinase 13, inhibin beta A, follistatin, and fibronectin mRNA levels were significantly reduced, whereas the expression of p21(CIP1), a major cell cycle inhibitory protein, was increased. The effects of ISF on the expression of IL-8 and p21(CIP1) mRNA and protein were validated at high and low ISF concentrations. Our data show that ISF inhibits the growth of PC-3 cells through modulation of cell cycle progression and the expression of genes involved in cell cycle regulation, metastasis, and angiogenesis.

Topics: DNA; Gene Expression Regulation, Neoplastic; Genistein; Humans; Interleukin-8; Isoflavones; Male; Oligonucleotide Array Sequence Analysis; Phytoestrogens; Prostatic Neoplasms; Soybean Proteins; Tumor Cells, Cultured

Based on evidence that phytoestrogens may protect against prostate cancer, we evaluated the associations between serum enterolactone concentration or dietary phytoestrogen intake and risk of prostate cancer.. In our Swedish population-based case-control study, questionnaire-data were available for 1,499 prostate cancer cases and 1,130 controls, with serum enterolactone levels in a sub-group of 209 cases and 214 controls. Unconditional logistic regression was performed to estimate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with risk of prostate cancer.. High intake of food items rich in phytoestrogens was associated with a decreased risk of prostate cancer. The OR comparing the highest to the lowest quartile of intake was 0.74 (95% CI: 0.57-0.95; p-value for trend: 0.01). In contrast, we found no association between dietary intake of total or individual lignans or isoflavonoids and risk of prostate cancer. Intermediate serum levels of enterolactone were associated with a decreased risk of prostate cancer. The ORs comparing increasing quartiles of serum enterolactone concentration to the lowest quartile were, respectively, 0.28 (95% CI: 0.15-0.55), 0.63 (95% CI: 0.35-1.14) and 0.74 (95% CI: 0.41-1.32).. Our results support the hypothesis that certain foods high in phytoestrogens are associated with a lower risk of prostate cancer.

Topics: 4-Butyrolactone; Diet; Health Behavior; Humans; Life Style; Lignans; Male; Phytoestrogens; Prostatic Neoplasms; Risk Factors; Sweden

The present study utilized microarray technology as a tool to elucidate the molecular signatures of soy-derived phytochemicals in the human androgen-responsive prostate cancer cell line LNCaP. Global gene expression pattern analysis of LNCaP cells exposed to 0, 1, 5, or 25 microM of the soy-derived phytochemicals equol and daidzein were conducted and compared. The data were further compared with previously generated data from exposure of LNCaP cells to the same doses of genistein, a soy isoflavone. Multidimensional scaling (MDS) analyses of the expression patterns suggest that these compounds exerted differential effects on gene expression in LNCaP cells. Further examination of specific gene changes revealed that these compounds differentially modulated genes in multiple cellular pathways, including the cell-cycle pathway genes. However, the three compounds also exerted similar effect on genes belonging to several other important cellular pathways. A universal effect of the three compounds on androgen-responsive genes, IGF-1 pathway gene, and MAP kinase-related pathway gene was observed. These results provide the foundation for establishing molecular signatures for equol, daidzein, and genistein. Moreover, these results also allow for the identification of candidate mechanism(s) by which soy phytochemicals and soy may act in prostate cancer cells.

Topics: Androgens; Cell Cycle; Cell Line, Tumor; Equol; Gene Expression; Gene Expression Profiling; Genistein; Glycine max; Humans; Insulin-Like Growth Factor I; Isoflavones; Male; Neoplasms, Hormone-Dependent; Oligonucleotide Array Sequence Analysis; Phytoestrogens; Prostatic Neoplasms; Receptor, IGF Type 1

It has been postulated that the R- and S-equol enantiomers have different biological properties given their different binding affinities for the estrogen receptor. S-(-)equol is produced via the bacterial conversion of the soy isoflavone daidzein in the gut. We have compared the biological effects of purified S-equol to that of racemic (R and S) equol on breast and prostate cancer cells of varying receptor status in vitro. Both racemic and S-equol inhibited the growth of the breast cancer cell line MDA-MB-231 (> or = 10 microM) and the prostate cancer cell lines LNCaP (> or = 5 microM) and LAPC-4 (> or = 2.5 microM). The compounds also showed equipotent effects in inhibiting the invasion of MDA-MB-231 and PC-3 cancer cells through matrigel. S-equol (1, 10, 30 microM) was unable to prevent DNA damage in MCF-7 or MCF-10A breast cells following exposure to 2-hydroxy-4-nonenal, menadione, or benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide. In contrast, racemic equol (10, 30 microM) prevented DNA damage in MCF-10A cells following exposure to 2-hydroxy-4-nonenal or menadione. These findings suggest that racemic equol has strong antigenotoxic activity in contrast to the purified S-equol enantiomer implicating the R-, rather than the S-enantiomer as being responsible for the antioxidant effects of equol, a finding that may have implications for the in vivo chemoprotective properties of equol.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Line, Tumor; Comet Assay; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; Equol; Female; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Receptors, Estrogen; Stereoisomerism

The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epidemiologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms.. We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales.. We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend <0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT).. Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.

Topics: Adult; Aged; Case-Control Studies; Diet; Estrogen Receptor beta; Food; Humans; Lignans; Male; Middle Aged; Phytoestrogens; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Prostatic Neoplasms; Risk Factors; Sweden

Dietary isoflavones, such as genistein and daidzein, are metabolised by the human gut microflora. Case-control studies have disclosed a link between the formation of the daidzein metabolite equol and prostate cancer risk. We evaluated the effects of genistein, daidzein and five metabolites on two prostate cancer cell lines by determining DNA integrity and cell growth. LNCaP cells contain the T877A androgen receptor mutation whereas Los Angeles prostate cancer (LAPC)-4 cells express the wild-type receptor, both of which may affect responses to isoflavones. DNA integrity was determined using the comet assay. Cell growth was assessed by staining DNA with 4',6'-diamidino-2-pheylindole hydrochloride. Endogenous steroid hormones, but not isoflavones, induced DNA strand breaks. Dihydrotestosterone stimulated the growth of both cell lines. 17beta-Oestradiol increased the growth of LNCaP but not LAPC-4 cells, pointing to an involvement of the T877A androgen receptor. Isoflavones did not stimulate growth in either prostate cancer cell line. However, the growth of LNCaP and LAPC-4 cells was suppressed by genistein (inhibitory concentration 50 % (IC50) 39.7 mumol/l, 37.2 mumol/l) and by equol (IC50 53.8 mumol/l, 35.1 mumol/l). O-desmethylangolensin inhibited the growth of LAPC-4 cells (IC50 45.2 mumol/l), but not of LNCaP cells. In conclusion, isoflavones do not damage DNA or promote growth of androgen-dependent prostate cancer cells. Several isoflavones, including the reduced daidzein metabolites equol and O-desmethylangolensin, suppress cancer cell growth. Taken together, these data suggest a contribution of gut-formed isoflavone metabolites to the beneficial effects of dietary isoflavones on prostate cancer risk.

Topics: Androgens; Antineoplastic Agents; Cell Division; Cell Line, Tumor; Comet Assay; Dihydrotestosterone; DNA Damage; DNA, Neoplasm; Estradiol; Genistein; Humans; Intestines; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms

Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.

Topics: Aged; Biomarkers; Diet; Genotype; Humans; Male; Middle Aged; Odds Ratio; Phytoestrogens; Polymorphism, Single Nucleotide; Prospective Studies; Prostatic Neoplasms; Risk Factors; United States

Phytoestrogens may reduce tumorigenesis in prostate cancer. We screened five phytoestrogens for their effect on cell growth and apoptosis in PWR-1E, LNCaP, PC-3, and DU145 prostate epithelial cells in vitro.. We assessed cell number, proliferation, and apoptosis using crystal violet assays, flow cytometric analysis, and TUNEL. Focusing specifically on apigenin we assessed the ability of calpain, serine protease, caspase, estrogen receptor, and ceramide synthase inhibitors to block apigenin induced apoptosis. We also analyzed caspase 3, 7, 8, 9, Bcl-2, Bax, Bid, and cytochrome C by Western analysis, and mitochondrial permeability and reactive oxygen species production by flow cytometry using mitosensor(TM) and DCFH-DA, respectively.. Apigenin and silybinin significantly reduced cell number, with apigenin inducing apoptosis in PWR-1E, LNCaP, PC-3, and DU145 cells. The PC-3 and DU145 cells were less susceptible to apigenin induced apoptosis then LNCaP and PWR-1E cells. The induction of apoptosis by apigenin was caspase dependent. Apigenin generated reactive oxygen species, a loss of mitochondrial Bcl-2 expression, mitochondrial permeability, cytochrome C release, and the cleavage of caspase 3, 7, 8, and 9 and the concomitant cleavage of the inhibitor of apoptosis protein, cIAP-2. The overexpression of Bcl-2 in LNCaP B10 cells reduced the apoptotic effects of apigenin.. Apigenin induces cell death in prostate epithelial cells using a mitochondrial mediated cell death pathway. Bcl-2 has a role in inhibiting apigenin induced cell death in prostate epithelial cells.

Topics: Amino Acid Chloromethyl Ketones; Apigenin; Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Cell Proliferation; Drug Interactions; Epithelial Cells; Flow Cytometry; Humans; In Situ Nick-End Labeling; Male; Mitochondria; Oligopeptides; Phytoestrogens; Prostatic Neoplasms; Protease Inhibitors; Reactive Oxygen Species; Silymarin

Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinoma; Cell Proliferation; Diet; Disease Models, Animal; Humans; Isoflavones; Lignans; Male; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Phytoestrogens; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Phytoestrogens may be associated with a reduced risk of hormone dependent neoplasms such as prostate and breast cancers. We tried to determine the validity of the association between serum phytoestrogen concentrations and dietary habits obtained from a food frequency questionnaire used in the Japan Collaborative Cohort Study (JACC Study) for Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho).. The subjects were 151 male controls who were selected for a nested case-control study for evaluating prostate cancer risk as part of the JACC Study. Dietary habits were determined using a food frequency questionnaire at baseline, and the concentrations of genistein, daidzein, and equol in frozenstored serum samples assayed in 2002 were compared.. Tofu intake showed a significant association with the serum concentrations of genistein and daidzein (Spearman's correlation coefficients (rs)=0.30 and 0.27, respectively), and miso soup showed a slight association with serum concentrations of these phytoestrogens. In contrast, serum concentrations of equol were not associated with dietary intake of tofu and miso soup. After adjustment for serum daidzein concentration, serum equol concentration was associated with the intake of foods containing fat, meat, and coffee, but not green tea.. Serum genistein and daidzein concentrations were significantly associated with dietary intake of tofu, and slightly with intake of miso soup. Consumption of fat, meat, and coffee may be associated with equol production by intestinal microflora in this sample set.

Topics: Adult; Aged; Case-Control Studies; Cohort Studies; Diet Surveys; Feeding Behavior; Genistein; Humans; Isoflavones; Japan; Male; Middle Aged; Nutritional Status; Phytoestrogens; Prostatic Neoplasms; Soy Foods; Surveys and Questionnaires

The purpose of this study was to examine whether a high serum concentration of phytoestrogens reduces the risk of prostate cancer in a case-control study nested in a community-based cohort in Japan (Japan Collaborative Cohort (JACC) Study). Information on lifestyles and sera of the subjects were collected in 1988-90, and they were followed up to 1999. Incident and dead cases of prostate cancer and controls were matched for study area and age. Phytoestrogens and sex hormones in sera stored at - 80 degrees C were measured in 2002. Of 14,105 male subjects of the cohort who donated their sera, 52 cases and 151 controls were identified. Three datasets were analyzed; 1) all subjects, 2) 40 cases and 101 controls after excluding subjects with low testosterone levels who were suspected of having had medical intervention, and 3) 28 cases and 69 controls with prostate specific antigen level of

Topics: Adult; Biomarkers, Tumor; Case-Control Studies; Humans; Isoflavones; Japan; Male; Middle Aged; Odds Ratio; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors

Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.5 M quercetin, baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin displaced > 85% of estradiol binding, whereas apigenin and resveratrol displaced > 40%. From growth inhibition studies in LNCaP cells, apigenin and curcumin were the most potent inhibitors of cell growth, and EGCG and baicalein were the least potent. In PC-3 cells, curcumin was the most potent inhibitor of cell growth, and EGCG was the least potent. In both cell lines, significant arrest of the cell cycle in S phase was induced by resveratrol and EGCG and in G2M phase by quercetin, baicalein, apigenin, genistein, and curcumin. Induction of apoptosis was induced by all of the 7 compounds in the 2 cell lines as shown by TUNEL and DNA fragmentation assays. Androgen responsiveness of the cell lines did not correlate with cellular response to the phytoestrogens. In conclusion, these 7 phytoestrogens, through different mechanisms, are effective inhibitors of prostate tumor cell growth.

Topics: Antineoplastic Agents, Hormonal; Catechin; Cell Cycle; Cell Division; Curcumin; DNA Fragmentation; Humans; Male; Phytoestrogens; Prostatic Neoplasms; Quercetin; Receptors, Estrogen; Resveratrol; Stilbenes; Tumor Cells, Cultured

To compare phytoestrogen tissue levels in men with small-volume benign prostatic hyperplasia (BPH), large-volume BPH, and prostate cancer (PCa).. Prostatic tissue samples of men consuming a Western diet who underwent surgery for BPH (n = 63) or PCa (n = 31) were collected and frozen at -40 degrees C. In the tissue samples, the enterolactone and genistein levels were determined in duplicate by monoclonal antibody-based immunoassays. We subsequently compared the tissue levels in patients with BPH and PCa and studied the impact of enterolactone and genistein on prostate volume.. The enterolactone tissue levels were comparable in patients with BPH and PCa and revealed no correlation to prostate volume. The genistein tissue levels tended to be lower in patients with PCa (median 8.4 ng/g dry weight) compared with the entire BPH group (11.0 ng/g dry weight; P = 0.072). In addition, the genistein tissue levels were significantly greater in men with small-volume BPH (median 20.9 ng/g dry weight) compared with those with large-volume BPH (8.8 ng/g dry weight; P = 0.023).. Our data suggest an involvement of genistein in the pathogenesis of BPH and, possibly, of PCa. The impact of enterolactone is currently unknown.

Topics: 4-Butyrolactone; Adenocarcinoma; Aged; Aged, 80 and over; Diet; Genistein; Humans; Lignans; Male; Middle Aged; Organ Size; Phytoestrogens; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

Phytoestrogens are nonsteroidal plant derived compounds with estrogenic activity that have been implicated in protecting against prostate cancer progression. We hypothesized that these compounds would alter cell number and increase the ability of antiandrogens to induce cell death in prostate cancer cells.. RWPE-1, LNCaP and PC-3 cells were treated with or without an extract of Belamcanda chinensis, 2 purified phytoestrogens derived from this extract (irigenin and tectorigenin) and the antiandrogen bicalutamide. We assessed the effect on cell number, proliferation and apoptosis.. Phytoestrogens (50 to 100 microM) and bicalutamide (10 to 50 microM) alone decreased the cell number in all 3 cell lines. Phytoestrogens (50 microM) combined with bicalutamide (10 microM) further decreased the number of RWPE-1 and PC-3 cells compared to these agents alone. Tectorigenin and irigenin inhibited the proliferation of RWPE-1, LNCaP and PC-3 cells, causing G1 arrest and the induction of p21WAF1 or p27 protein expression, whereas bicalutamide induced apoptosis in a dose dependent manner in all 3 cell lines. Phytoestrogens did not have antiandrogenic activity.. These in vitro studies demonstrate a role for tectorigenin and irigenin in regulating prostate cancer cell number by inhibiting proliferation through cell cycle regulation.

Topics: Cell Division; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Iridaceae; Isoflavones; Male; Phytoestrogens; Plant Extracts; Prostatic Neoplasms; Tumor Cells, Cultured

Enterolactone, a phytoestrogen produced by the intestinal microflora from precursors in plant foods, has been postulated to protect against hormone-dependent cancers. We studied the association between plasma enterolactone and risk of prostate cancer.. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured by time-resolved fluoroimmunoassay in plasma taken from 265 men who were diagnosed with prostate cancer at a mean time of 5 years after blood collection, and in plasma from 525 control men, matched for age and date of blood collection.. There was no significant association between quartiles of plasma enterolactone and risk of prostate cancer. Odds ratios for prostate cancer, estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles were 1.00 (referent), 0.81 (95% confidence interval 0.52-1.27), 1.03 (0.67-1.58), and 1.22 (0.80-1.86). Adjustments for body mass index (BMI), smoking status and stratification for age, lag time, storage time and tumour characteristics did not materially alter risk estimates. Men with very low enterolactone levels, however, had significantly higher risk of prostate cancer, odds ratio for bottom decile versus all other deciles was 1.68 (1.03-2.74).. Our results do not support the hypothesis that enterolactone formed from dietary lignans protects against prostate cancer.

Topics: 4-Butyrolactone; Cohort Studies; Humans; Life Style; Lignans; Male; Middle Aged; Obesity; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Risk; Smoking; Sweden

In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D(3) for antimitotic action is determined through the activity of the two enzymes CYP24 and CYP27B1, viz. 25-hydroxyvitamin D-24-hydroxylase and 25-hydroxyvitamin D-1alpha-hydroxylase. High performance liquid chromatography (HPLC) analysis of [(3)H]25(OH)D(3) metabolism in human prostate cancer DU-145 cells revealed that genistein and other isoflavonoids, such as dihydrogenistein and daidzein, as well as the antiestrogenic compound ICI 182,780, inhibited Vitamin D-metabolizing enzyme activities. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only in case of genistein this was due to transcriptional inhibition of CYP24 and CYP27B1 gene expressions. In case of CYP27B1, reduction of gene activity involves histone deacetylation because genistein was inactive in the presence of the histone deactylase inhibitor trichostatin A. In contrast, under the same condition, CYP24 gene activity was largely suppressed. In summary, our results suggest that a combined effect of genistein and trichostatin A could increase the responsiveness of human prostate cancer cells to the antiproliferative action of 1,25-dihydroxyvitamin D(3).

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Cell Division; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Fulvestrant; Genistein; Histone Deacetylases; Humans; Hydroxamic Acids; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Steroid Hydroxylases; Time Factors; Transcription, Genetic; Tumor Cells, Cultured; Vitamin D; Vitamin D3 24-Hydroxylase

Though 1,25-dihydroxyvitamin D3 (1,25-D3) as well as some vitamin D analogs have an antimitotic as well as a differentiating action, therapeutic application in tumor patients is still precluded due to their hypercalcemic action at the necessary concentration. Our observation that early during progression, colon tumor cells express CYP27B1, the enzyme essential for 1,25-D3 synthesis, as well as the vitamin D receptor (VDR) at a higher level than normal colon cells led to the speculation that, by induction of this expression, a physiological defense against tumor progression could be activated and enhanced. In some Asian countries where soy products are a main staple, prostate and breast tumor incidence is extremely low. We speculated that this could be due to regulation of CYP enzymes by phytoestrogens present in soy such as genistein. In prostate tumor cells, the 1,25-dihydroxyvitamin D3 catabolizing enzyme CYP24 is frequently highly expressed. We were able to demonstrate that genistein down-regulates expression of CYP24 to almost nil, which would result in enhancement of local 1,25-D3 levels and improved mitotic control of tumor cells.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Colon; Colonic Neoplasms; Cytochrome P-450 Enzyme System; Dietary Proteins; Estrogens, Non-Steroidal; Gene Expression; Genistein; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Soybean Proteins; Steroid Hydroxylases; Vitamin D; Vitamin D3 24-Hydroxylase

The mortality of clinical prostate cancer is lower in Asian populations than in American or European men. Asian men typically consume more soy than their Western counterparts, leading to the investigation of individual components, particularly phytoestrogens, as protective factors against prostate cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of prostate cancer in animal models, but the underlying biological action remains to be elucidated. The purpose of this investigation was to identify the effects of the phytoestrogen, genistein and the synthetic estrogen diethylstilbestrol (DES), as a control, on development and function of the rat dorsolateral prostate (DLP) when given in the diet. The effects of testosterone and dihydrotestosterone (DHT) injections were also tested. Analysis of individual lobes of the DLP revealed that 1000 mg/kg, but not 250 mg/kg, of a genistein AIN-76A diet slightly reduced lateral prostate type 1 (LP1) bud perimeter. However, expression of the secretory dorsal protein 1 (DP1) and 5alpha-reductase type II activity were not altered in the prostate. This suggested that prostate differentiation, and not toxicity, had occurred. DES in the diet reduced and testosterone injections elevated relative prostate weights and perimeters of the dorsal, LP1, lateral prostate type 2 and DP1 expression. DHT increased relative prostate weights but did not significantly increase individual lobe perimeter. Unlike DES, maximally tolerated doses of genistein in the diet were not toxic to the rat prostate.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgen-Binding Protein; Animals; Anticarcinogenic Agents; Diethylstilbestrol; Dihydrotestosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Genistein; Glycine max; Growth Inhibitors; Humans; Isoflavones; Male; Organ Size; Phytoestrogens; Plant Preparations; Prostate; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Testosterone

Asian individuals have much lower incidences of prostate and breast cancer than populations from Western developed countries. They also consume a lower fat, higher fiber diet, with a large intake of phytoestrogens. These phytoestrogens may protect against hormone-dependent cancers and other diseases. Our study used established gas chromatography-mass spectrometry (GC-MS) methodologies to measure the concentrations of four phytoestrogens (daidzein, genistein, equol and enterolactone) in serum samples obtained from Japanese men (n = 102) and women (n = 125) > 40 y old. The results were compared with those obtained with samples from the UK. The Japanese men and women had higher (P < 0.001) concentrations of circulating daidzein, genistein and equol than individuals from the UK. The mean concentration of genistein in Japanese men, for example, was 492.7 nmol/L, compared with 33.2 nmol/L in men from the UK. The two populations, however, had similar serum concentrations of enterolactone. Furthermore, 58% of the Japanese men and 38% of the Japanese women had equol concentrations > 20 nmol/L, compared with none of the UK men and 2.2% of the UK women. These results support previously published GC-MS results from studies with low numbers of samples.

Topics: 4-Butyrolactone; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Chromans; Diet; Equol; Estrogens, Non-Steroidal; Female; Gas Chromatography-Mass Spectrometry; Genistein; Humans; Isoflavones; Japan; Lignans; Male; Middle Aged; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; United Kingdom

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

The ability to interfere with prostate carcinogenesis, and as a consequence, prevent prostate cancer with drugs is the basis for chemoprevention. The prostate contains estrogen receptors in both the stroma and epithelium. Both animal models and human epidemiologic studies have implicated estrogens as an initiator of prostate cancer. In the aging male, prostate cancer occurs in an environment of rising estrogen and decreasing androgen levels. Selective estrogen receptor modulators (SERMs) have shown the ability to prevent (GTx-006 [acapodene]) and treat (GTx-006 and arzoxifene) prostate cancer, suggesting that they may be used in prostate cancer chemoprevention. A phase 2 clinical trial using GTx-006 for prostate cancer chemoprevention is currently being conducted.

Topics: Age Factors; Androgens; Anticarcinogenic Agents; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogens; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Phytoestrogens; Piperidines; Plant Preparations; Prostate; Prostatic Neoplasms; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Thiophenes

Topics: Diet; Dietary Fats; Estrogens, Non-Steroidal; Humans; Incidence; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; United States; Vegetables

In this study, we investigated whether dietary intervention could inhibit tumor growth of an androgen-sensitive human prostatic cancer.. LNCaP cells were transplanted subcutaneously in nude-mice. The animals were then put on different diets and tumor take, tumor growth and prostate specific antigen (PSA) secretion were studied during 9 weeks.. Palpable tumors developed in 75% of the tumor-cell injected sites in animals fed a control diet (corn starch, sucrose, etc.) whereas, for animals given rye bran (RB), ethyl acetate extraction from rye bran supplemented cellulose based diets (CCEE), palpable tumors were seen in only 30% and for soy protein based diets (SCC) 50% of the transplantation sites, respectively. The tumors that grew to palpable size in the rye (RB) and soy (SCC) groups were smaller and secreted less PSA than those in the control group. In the rye and soy groups tumor cell apoptosis was increased, but cell proliferation was unaffected. Addition of fat to the rye diet reduced its effect on prostate cancer growth.. Factors in rye bran and soy protein may inhibit prostate cancer growth. The effect is more apparent for rye than for soy. Further studies are needed to identify the effective substances and to explore the mechanism of action.

Topics: Adenocarcinoma; Animals; Apoptosis; Cell Division; Dietary Fiber; Dietary Proteins; Eating; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Neoplasm Transplantation; Phytoestrogens; Plant Preparations; Prostate-Specific Antigen; Prostatic Neoplasms; Secale; Soybean Proteins

Epidemiological surveys recorded that men in the Orient (Japan and China) consuming diets high in soy food were at low risk of developing clinical prostate cancer, compared to a relatively high risk among men in the West who consumed diets low in soy food. Soybeans contain phytoestrogens (isoflavones) with many recorded anticancer mechanisms. The Lobund-Wistar (L-W) rat is a unique model system: approximately 30% develop metastasizing adenocarcinomas spontaneously in the anterior prostate-seminal vesicle complex (P-SV), from which the tumors expand into the dorsolateral lobes. L-W rats are inherently predisposed, possibly by unusually high levels of circulating testosterone (T), to develop P-SV tumors which are T-dependent in the early stages and T-independent in advanced stages of tumorigenesis.. L-W rats were fed two diets from age 2-24 months: 1) natural ingredient diet L-485 (Harlan TekLad Diets, Madison, WI) containing soy meal, or 2) a modified starch-casein diet in which soy protein isolate/isoflavones (SPII) replaced casein as a source of protein.. At age 24 months, 3 of 99 (3%) rats on diet SPII and 30 of 100 (30%) rats on diet L-485 developed spontaneous P-SV cancers. Rats on the SPII diet manifested a significant reduction of circulating T, approaching physiological levels. Failure of the rats on diet L-485 to prevent P-SV cancer development suggests that soy meal contained a factor(s) that blocked the antiandrogenic action of the phytoestrogen.. The spontaneous development of P-SV cancers was significantly prevented in L-W rats consuming the SPII diet from age 2-24 months, possibly through an agonist effect of the soy-derived phytoestrogens.

Topics: Animals; Estrogens, Non-Steroidal; Glycine max; Growth; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Rats; Rats, Wistar; Soybean Proteins; Testosterone

Male sex, advancing age, racial origin, affected first degree relatives and the ubiquitous 'Western lifestyle' have all been cited as significant risk factors for the development of prostate cancer. Numerous epidemiological studies have been undertaken and others are in place to try and identify specific risk factors but diet has not been conclusively implicated to date. Most of the current prostate research suggests that the roles of dietary fat, soy proteins, selenium and possibly vitamin E are greater in determining the progression or stimulation of established tumours rather than in the development of new tumours per se. Certainly the hypothesis casts some light on the geographic variations of the disease. What part diet and nutritional factors play in the overall jigsaw of prostate cancer development needs to be further established. It is an area that will undoubtedly attract much more research interest in future years.

Topics: Diet; Dietary Fats; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Nutritional Physiological Phenomena; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors

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

In the last several years, attention has been focused on comparing the Western diet, which is rich in fat, protein, and refined carbohydrates, with the Asian diet, which is rich in phytoestrogens, as a possible explanation for the contrasting rates of clinically relevant prostate cancer. Phytoestrogens, plant-derived nutrients, include several isoflavones, flavonoids, lignans, phytosterols, and coumestans, some of which have been postulated as having anticarcinogenic properties. Using a new database, we examined the role of phytoestrogen intake and prostate cancer risk in 83 Caucasian cases and 107 controls. Controls reported consuming higher amounts of foods containing genistein, daidzein, and coumestrol and lower amounts of foods containing campesterol and stigmasterol. Multivariate analysis, after adjustment for age, family history of prostate cancer, alcohol consumption, and total calorie intake, showed an inverse association between coumestrol (p = 0.03) and daidzein (p = 0.07) and prostate cancer risk. Genistein, the most studied phytoestrogen, showed a slight protective effect (p = 0.26). However, a positive association was found between campesterol (p = 0.08) and stigmasterol (p = 0.03) and risk of prostate cancer. These results are suggestive of a possible relationship between phytoestrogen intake and prostate cancer risk. Larger comprehensive studies are needed to further refine the role of phytoestrogen intake in prostate cancer risk.

Topics: Anticarcinogenic Agents; Case-Control Studies; Cholesterol; Databases, Factual; Diet Records; Estrogens, Non-Steroidal; Genistein; Humans; Isoflavones; Male; Middle Aged; Multivariate Analysis; Nutrition Assessment; Phytoestrogens; Phytosterols; Plant Preparations; Prostatic Neoplasms; Risk Factors; Stigmasterol; Surveys and Questionnaires; Texas

Since prostate cancer (PC) development involves a combination of genetic predisposition and promotional mechanisms, especially the metabolic conversion of testosterone to 5alpha dihydrotestosterone (DHT) by 5alpha reductase, how do mechanisms in man relate to prostate-seminal vesicle (P-SV) tumor development in Lobund-Wistar (L-W) rats? The disease in man and in L-W rats shares developmental mechanisms and characteristics to the extent that prevention of P-SV tumors in L-W rats could be predictive of similar results in man. The epidemiology of PC in man and P-SV tumors in L-W rats indicates that both are hormone-related diseases based on genetic predisposition, high production of androgens (which are activated to DHT by 5alpha reductase), and early development of androgen-dependent and metastasizing late androgen-independent stages of adenocarcinomas, all after long latency periods.. L-W rats at risk of developing spontaneous or induced P-SV tumors were subjected to putative antitumor agents or procedures. These included dietary restriction, testosterone ablation, soybean-derived isoflavones, antiangiogenic linomide, tamoxifen, and a vitamin D analogue.. L-W rats subjected to 1) early onset of dietary restriction manifested suppression of spontaneous and induced development of P-SV tumors; 2) testosterone-ablation by nonesterified DHT (NE-DHT) suppressed early onset of induced P-SV tumors and to a lesser extent late onset of spontaneous tumors; 3) diets containing soy protein isolate (high isoflavones) manifested marginal suppressive effects against induced P-SV tumors, but in 12-month-old rats, the development of spontaneous tumors was reduced in incidence; 4) early administrations of antiangiogenic linomide suppressed development of induced P-SV tumors and of transplanted prostate adenocarcinoma III (PA-III) tumors, but linomide had little antitumor effect against large advanced stage tumors; and 5) tamoxifen and vitamin D analogue suppressed development of P-SV tumors. Results in conditions 1-3 were negative when tested against PA-III tumors.. Developing stages of P-SV tumors were prevented in L-W rats with autochthonous spontaneous and induced tumors, but most of the agents tested were of no therapeutic benefit against advanced-stage and transplanted PA-III tumors. However, early administrations of antiangiogenic linomide suppressed early growth of induced and transplanted PA-III tumors.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Disease Susceptibility; Estrogens, Non-Steroidal; Glycine max; Hydroxyquinolines; Isoflavones; Male; Neovascularization, Pathologic; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Rats; Rats, Wistar; Tamoxifen; Testosterone; Vitamin D

Topics: Animals; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Mice; Mice, Knockout; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Receptors, Estrogen

Resveratrol, a natural phytoestrogen, has been reported to promote differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation of prostate cancer cell lines. In the present study we tested the effects of resveratrol on the increased proliferation of human AHTO-7 osteoblastic cell line induced by conditioned media (CM) from a panel of carcinoma cell lines. This compound was found to modulate AHTO-7 proliferation in a tamoxifen-sensitive mechanism at lower concentrations, but failed to induce the osteoblast differentiation marker alkaline phosphatase (ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition) upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM) cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced. Direct addition of resveratrol affected only supernatants of cell lines (<25% inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts. Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations exceeding 5 microM, altered cell cycle distribution of all prostate cancer cell lines in concentrations as low as 0.5 microM, but did not inhibit the production of osteoblastic factors by these lines. In conclusion, resveratrol failed to induce ALP activity as marker of osteoblast differentiation in human osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic carcinoma-derived growth factors in concentrations significantly lower than those to reduce growth of cancer cells, thus effectively modulating tumor - osteoblast interaction.

Topics: Alkaline Phosphatase; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Renal Cell; Cell Differentiation; Cell Line; Culture Media, Conditioned; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Kidney Neoplasms; Lung; Male; Osteoblasts; Pancreatic Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Resveratrol; Stilbenes; Tamoxifen; Tumor Cells, Cultured

Topics: Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Soybean Proteins

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms

Phytoestrogens are biologically active plant compounds with both oestrogenic and antioestrogenic actions, and communities whose diets are rich in phytoestrogens have a lower incidence of prostate cancer. A 66-year-old man took phytoestrogen 160 mg (4 x 40-mg tablets) daily for one week before radical prostatectomy for moderately high-grade adenocarcinoma. The resected specimen showed prominent apoptosis, typical of a response to high-dose oestrogen therapy and suggestive of tumour regression. There were no adverse side effects. Studies of the effects of phytoestrogens in prostate cancer may be warranted.

Topics: Adenocarcinoma; Aged; Combined Modality Therapy; Estrogens, Non-Steroidal; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatectomy; Prostatic Neoplasms