Impact of Soy Isoflavones on the Epigenome in Cancer Prevention

Isoflavones (IF) such as genistein are cancer preventive phytochemicals found in soy and other legumes. Epidemiological studies point to a reduced risk for hormone‑dependent cancers in populations following a typical Asian diet rich in soy products. IF act as phytoestrogens and prevent tumorigenesis in rodent models by a broad spectrum of bioactivities. During the past 10 years, IF were shown to target all major epigenetic mechanisms regulating gene expression, including DNA methylation, histone modifications controlling chromatin accessibility, and non-coding RNAs. These effects have been suggested to contribute to cancer preventive potential in in vitro and in vivo studies, affecting several key processes such as DNA repair, cell signaling cascades including Wnt-signaling, induction of apoptosis, cell cycle progression, cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), metastasis formation and development of drug-resistance. We here summarize the state-of-the-art of IF affecting the epigenome in major hormone-dependent, urogenital, and gastrointestinal tumor types and in in vivo studies on anti-cancer treatment or developmental aspects, and short-term intervention studies in adults. These data, while often requiring replication, suggest that epigenetic gene regulation represents an important novel target of IF and should be taken into consideration when evaluating the cancer preventive potential of IF in humans.     

A versatile synthesis of [2,3,4‐13C3]isoflavones

A flexible synthetic method is presented, which allows all the key isoflavones (daidzein, genistein, glycitein, formononetin and biochanin A) to be prepared in ¹³C‐labelled form via the same route, involving the thallium(III)‐mediated oxidative rearrangement of a key chalcone intermediate. This method results in the incorporation of ¹³C atoms at the 2, 3 and 4 positions of the isoflavone skeleton. We also report the first syntheses of ¹³C‐labelled versions of the daidzein metabolites, equol and ODMA. Copyright © 2009 John Wiley & Sons, Ltd.     

Phytoestrogenic isoflavonoids in epidemiologic and clinical research

Isoflavones (IFLs) are natural products to which humans have been traditionally exposed predominantly through soy foods; more recently humans are also exposed to them through soy protein addition to processed foods or through supplements. They are structurally similar to steroidal estrogens and can exert estrogenic or antiestrogenic effects depending on their concentrations and on the tissue considered. These properties qualify IFLs to be classified as phytoestrogens and are believed to account for many of the biological effects observed for soy and/or IFL exposure including benefits for bone and heart health or prevention of menopausal symptoms and certain types of cancer. In order to evaluate the function of IFLs, alone or when exposure happens through soy intake, pharmacokinetics and bioavailability are critical issues to be considered in epidemiologic and clinical research. For this purpose precise, accurate, robust, fast, and affordable techniques for IFL analyses are required. Copyright © 2009 John Wiley & Sons, Ltd.     

Phytoestrogen action in the adult and developing brain

Abstract Soy isoflavonoids are plant phytoestrogens available as dietary supplements and are increasingly advocated as a natural alternative to oestrogen replacement therapy. As weak oestrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model to investigate the actions of endocrine disruptors. Here, the activational and organisational effects of these compounds on the brain are reviewed. In spite of their preferential affinity for oestrogen receptor (ER)beta in vitro, isoflavonoids act in vivo through both ERalpha and ERbeta. Their neurobehavioural actions are largely anti-oestrogenic, either antagonising or producing an action in opposition to that of oestradiol. Small, physiologically relevant exposure levels can alter oestrogen-dependent gene expression in the brain and affect complex behaviour in a wide range of species. The implications for these findings in humans, and particularly in infants, largely remain uninvestigated but are a subject of increasing public interest.     

Soyfood intake and breast cancer survival: a followup of the Shanghai Breast Cancer Study

Soy and its constituents have been shown in many in vivo and in vitro studies and in some epidemiological studies to have anti-cancer effects. Some soy constituents, however, also stimulate cell proliferation, which has raised concerns in promoting soy intake among breast cancer survivors. To investigate whether soy intake may be associated with breast cancer survival, we evaluated data from a cohort of 1459 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. Usual soy food intake was assessed using a validated food frequency questionnaire at baseline. The median follow-up time for this cohort of women was 5.2 years. We found that soy intake prior to cancer diagnosis was unrelated to disease-free breast cancer survival (adjusted hazard ratio [HR]=0.99, 95% confidence interval [CI], 0.73–1.33 for the highest tertile compared to the lowest tertile). The association between soy protein intake and breast cancer survival did not differ according to ER/PR status, tumor stage, age at diagnosis, body mass index (BMI), waist to hip ratio (WHR), or menopausal status. Additionally, the soy-survival association did not appear to vary according to XbaI or PvuII polymorphisms in ER-alpha, or C(14206)T, G(25652)A, or A(50766)G polymorphisms in ER-beta. These data suggest that soyfoods do not have an adverse effect on breast cancer survival.     

Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Recent diet and breast cancer risk: the California Teachers Study (USA)

Objective: The impact, if any, on breast cancer risk of modifying adult dietary intake is an area of much interest. We take the opportunity to address the relationship between recent adult diet and breast cancer risk during the first two years of follow-up of the large California Teachers Study cohort. Methods: Of the 111,526 at-risk cohort members who resided in California and completed a baseline dietary assessment, 711 were diagnosed with invasive breast cancer after joining the cohort and before January 1998. Average daily nutrient intake was computed based on a food-frequency questionnaire assessing usual dietary intake and portion size during the year prior to joining the cohort. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence utilized a variety of data sources. Cox proportional hazards models were used to calculate relative hazards. Results: The following components of recent dietary intake were not associated with breast cancer risk: energy, fat, fiber, antioxidant vitamins, and phytoestrogens. Only recent average alcohol consumption of 20 or more grams per day (approximately two or more glasses of wine) was associated with increased risk (RR = 1.5, 95% CI: 1.2–2.0 compared to non-drinkers; p _trend = 0.01 across quintiles). Conclusion: With the exception of alcohol consumption, this study provides no evidence that recent macro- or micronutrient composition of adult diet is likely to have a direct effect on breast cancer risk. Some reduction of alcohol consumption among those consuming more than one drink per day may be beneficial.     

Synergistic effects induced by cycloprodigiosin hydrochloride and epirubicin on human breast cancer cells

Hormone replacement therapy, which is a common menopausal treatment, is contraindicated in women with breast cancers due to concerns regarding the potential for breast cell proliferation. As such, there is a need for alternative methods for treating menopausal symptoms. To determine the influence of one such alternative, black cohosh (Cimicifuga racemosa [CR]), on estrogen-dependent mammary cancers, we conducted an in vitro investigation of the effect of an isopropanolic CR-extract on the proliferation of estrogen receptor-positive breast cancer cells. The experiments were performed using the human breast adenocarcinoma (MCF-7) cell test system, an established in vitro model for estrogen-dependent tumors. The influence of CR-extract on the proliferation of the MCF-7 cells was determined by measuring the incorporation of radioactively labeled thymidine. Under estrogen-deprived conditions, the CR-extract (10^–3–10^–5 dilutions) significantly inhibited MCF-7 cell proliferation. Additionally, application of the CR-extract inhibited estrogen-induced proliferation of MCF-7 cells. Moreover, the proliferation-inhibiting effect of tamoxifen was enhanced by the CR-extract. Such data that suggest a non-estrogenic, or estrogen-antagonistic effect of CR on human breast cancer cells lead to the conclusion that CR treatment may be a safe, natural remedy for menopausal symptoms in breast cancer.     

木脂素——一类重要的天然植物雌激素

木脂素是一类具有弱雌激素和抗雌激素特性的重要植物雌激素。木脂素具有多种生物活性,包括抗氧化、抗病毒和抗肿瘤等。木脂素对激素依赖型疾病,特别是乳腺癌、前列腺癌和良性前列腺增生有预防作用。然而,对诸如从食物中获得的木脂素在体内的代谢物是否具有基因毒性、木脂素的具体抗癌机制和木脂素在体内起作用的剂量等许多重要科学问题仍不清楚。作者综述了木脂素的分类、分布、代谢过程、药理活性和测定方法,并对木脂素的未来研究方向进行了展望。     

植物雌激素在雌性生殖系统中的抗氧化作用

目的 探讨植物雌激素白藜芦醇、染料木黄酮和大豆黄酮在人类宫颈癌细胞HeLa、乳腺癌细胞MCF7和卵巢癌细胞SK-OV-3中对抗氧化信号通路的影响.方法 将抗氧化响应元件ARE报告基因转染入HeLa、MCF7和SK-OV-3细胞.稳定表达ARE荧光报告基因后,细胞培养基中分别加入50、25、12.5、6.25、3.125、1.56和0μmol/L的3种植物雌激素,检测ARE诱导倍数的变化.分别检测3种植物雌激素24h处理后诱导细胞中抗氧化基因Nrf2、SOD1、SOD2、SOD3、HO-1、GSTm、GSTp、NQO1、CAT和CLGC等的mRNA表达水平.在MCF7细胞中,检测25μmol/L的白藜芦醇和大豆黄酮对野生型Keap1蛋白抑制Nrf2-ARE表达的影响.结果 在MCF7、HeLa和SK-OV-3细胞中,3种植物雌激素均能诱导ARE报告基因的高表达,并促进Nrf2、SOD3、GSTp、CAT和CLGC等抗氧化基因的高表达.同时,25μmol/L的白藜芦醇和大豆黄酮在MCF7细胞中能够有效淬灭Keap1蛋白对ARE表达的抑制作用.结论 植物雌激素白藜芦醇、染料木黄酮和大豆黄酮能够在人类宫颈癌细胞HeLa、乳腺癌细胞MCF7和卵巢癌细胞SK-OV-3中诱导抗氧化信号通路.诱导效应具有剂量依赖性和组织特异性.转录调控蛋白Keap1可能参与了诱导反应机制.