phytoestrogens and kaempferol

Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3'-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Genistein; Humans; Indoles; Kaempferols; Neoplasm Metastasis; Neoplasms; Phytoestrogens; Resveratrol; Stilbenes

Beer is one of the earliest human inventions and globally the most consumed alcoholic beverage in terms of volume. In addition to water, the 'German Beer Purity Law', based on the Bavarian Beer Purity Law from 1516, allows only barley, hops, yeasts and water for beer brewing. The extracts of these ingredients, especially the hops, contain an abundance of polyphenols such as kaempferol, quercetin, tyrosol, ferulic acid, xanthohumol/isoxanthohumol/8-prenylnaringenin, α-bitter acids like humulone and β-bitter acids like lupulone. 8-prenylnaringenin is the most potent phytoestrogen known to date. These compounds have been shown to possess various anti-bacterial, anti-inflammatory, anti-oxidative, anti-angiogenic, anti-melanogenic, anti-osteoporotic and anti-carcinogenic effects. Epidemiological studies on the association between beer drinking and skin disease are limited while direct evidence of beer compounds in clinical application is lacking. Potential uses of these substances in dermatology may include treatment of atopic eczema, contact dermatitis, pigmentary disorders, skin infections, skin ageing, skin cancers and photoprotections, which require an optimization of the biostability and topical delivery of these compounds. Further studies are needed to determine the bioavailability of these compounds and their possible beneficial health effects when taken by moderate beer consumption.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Beer; Coumaric Acids; Cyclohexenes; Flavanones; Flavonoids; Humans; Kaempferols; Phenylethyl Alcohol; Phytoestrogens; Propiophenones; Quercetin; Skin; Skin Diseases; Terpenes; Xanthones

Saraca asoca (Roxb.) de Wilde, Ashok, is a popular traditional plant used for gynecological disorders. In India, the juice of Ashok flowers is traditionally consumed as a tonic by women in case of uterine disorders. But despite the use, its estrogenic potency is not yet evaluated and thus lacks the scientific recognition and acclaim.. This study is designed to investigate the estrogenic potential of standardized ethanolic extract of Saraca asoca flowers (SAF) using ovariectomized (OVX) female albino Wistar rat model.. Saraca asoca flowers were extracted in ethanol using hot maceration technique and the extract was standardized in terms of content of four phytoestrogens like quercetin, kaempferol, β-sitosterol and luteolin using HPTLC technique. Safety of the extract was evaluated at a dose of 2000mg/kg body weight in female albino Wistar rats as per the OECD guidelines. Bilateral ovariectomy surgery was performed for the excision of both the ovaries. The OVX animals were treated with the ethanolic extract of SAF at three dose levels- 100mg/kg, 200mg/kg and 400mg/kg body weight in distilled water as a vehicle, orally once a day for two weeks. Estradiol valerate was employed as a modern drug for comparative evaluation of the results. Estrogenic potency was studied by assaying the activities of serum and plasma marker enzymes and hormones viz. G6PDH, LDH, 17β-estradiol, progesterone along with cholesterol, triglycerides and HDL, and vaginal cornification. The uterotrophic effect was evaluated by studying the histoarchitecture of the uterus, effect on uterine weight and changes in the levels of uterine glycogen content.. HPTLC revealed the presence of markers like quercetin, kaempferol, β-sitosterol and luteolin from the ethanolic extract of SAF. The content of the four markers was found to be 1.543mg/g, 0.924mg/g, 4.481mg/g and 2.349mg/g, respectively. SAF extract was found to be safe at an oral dose of 2000mg/kg body weight in rats. Among the three doses administered to ovariectomized rats, treatment with high dose was found to be more efficacious when compared with ovariectomized rats.. The findings of this study firmly support the estrogenic potency of ethanolic extract of SAF which may be by the reason of phytoestrogens.

Topics: Administration, Oral; Animals; Biomarkers; Chromatography, Thin Layer; Estradiol; Estrogen Replacement Therapy; Ethanol; Fabaceae; Female; Flowers; Glucosephosphate Dehydrogenase; Glycogen; Kaempferols; L-Lactate Dehydrogenase; Lipids; Luteolin; Medicine, Ayurvedic; Organ Size; Ovariectomy; Phytoestrogens; Phytotherapy; Plant Extracts; Plants, Medicinal; Progesterone; Quercetin; Rats, Wistar; Sitosterols; Solvents; Uterus; Vagina

As a phytoestrogen, kaempferol is known to play a chemopreventive role inhibiting carcinogenesis and cancer progression. In this study, the influences of triclosan, an anti-bacterial agent recently known for an endocrine disrupting chemical (EDC), and kaempferol on breast cancer progression were examined by measuring their effects on epithelial-mesenchymal transition (EMT) and metastatic-related behaviors of MCF-7 breast cancer cells. Morphological changes of MCF-7 cells were observed, and a wound-healing assay was performed after the treatment of triclosan and kaempferol. The effects of triclosan and kaempferol on protein expression of EMT-related markers such as E-cadherin, N-cadherin, Snail, and Slug and metastasis-related markers such as cathepsin B, D, MMP-2 and -9 were investigated by Western blot assay. In microscopic observations, triclosan (10

Topics: Anti-Infective Agents, Local; Antineoplastic Agents; Breast Neoplasms; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Kaempferols; MCF-7 Cells; Neoplasm Invasiveness; Phytoestrogens; Receptors, Estrogen; Triclosan

Phytoestrogens are plant-derived compounds that functionally and structurally mimic mammalian estrogens. Phytoestrogens have broad inhibitory activities toward several steroidogenic enzymes, such as the 17β-hydroxysteroid dehydrogenases (17β-HSDs), which modulate the biological potency of androgens and estrogens in mammals. However, to date, no crystallographic data are available to explain phytoestrogens binding to mammalian 17β-HSDs. NADP(H)-dependent 17β-HSD from the filamentous fungus Cochliobolus lunatus (17β-HSDcl) has been the subject of extensive biochemical, kinetic and quantitative structure-activity relationship studies that have shown that the flavonols are the most potent inhibitors. In the present study, we investigated the structure-activity relationships of the ternary complexes between the holo form of 17β-HSDcl and the flavonols kaempferol and 3,7-dihydroxyflavone, in comparison with the isoflavones genistein and biochanin A. Crystallographic data are accompanied by kinetic analysis of the inhibition mechanisms for six flavonols (3-hydroxyflavone, 3,7-dihydroxyflavone, kaempferol, quercetin, fisetin, myricetin), one flavanone (naringenin), one flavone (luteolin), and two isoflavones (genistein, biochanin A). The kinetics analysis shows that the degree of hydroxylation of ring B significantly influences the overall inhibitory efficacy of the flavonols. A distinct binding mode defines the interactions between 17β-HSDcl and the flavones and isoflavones. Moreover, the complex with biochanin A reveals an unusual binding mode that appears to account for its greater inhibition of 17β-HSDcl with respect to genistein. Overall, these data provide a blueprint for identification of the distinct molecular determinants that underpin 17β-HSD inhibition by phytoestrogens.

Topics: 17-Hydroxysteroid Dehydrogenases; Ascomycota; Binding Sites; Biocatalysis; Crystallography, X-Ray; Databases, Protein; Dietary Supplements; Enzyme Inhibitors; Flavonoids; Fungal Proteins; Genistein; Holoenzymes; Hydroxylation; Kaempferols; Models, Molecular; Molecular Conformation; Phytoestrogens; Protein Conformation; Recombinant Proteins; Structure-Activity Relationship

Phytoestrogens are of interest because of their reported beneficial effects on many human maladies including cancer, neurodegeneration, cardiovascular disease and diabetes. As data on phytoestrogens continues to accumulate, it is clear that there is significant overlap in the cellular effects elicited by these various compounds. Here, we show that one mechanism by which a number of phytoestrogens achieve their growth inhibitory and cytoprotective effects is via induction of the mitochondrial manganese superoxide dismutase (MnSOD). Eight phytoestrogens, including resveratrol, coumestrol, kaempferol, genistein, daidzein, apigenin, isoliquirtigenin and glycitin, were tested for their ability to induce MnSOD expression in mouse C2C12 and primary myoblasts. Five of these, resveratrol, coumestrol, kaempferol, genistein and daidzein, significantly increased MnSOD expression, slowed proliferative growth and enhanced stress resistance (hydrogen peroxide LD50) . When siRNA was used to prevent the MnSOD induction by genistein, coumestrol or daidzein, none of these compounds exerted any effect on proliferative growth, and only the effect of coumestrol on stress resistance persisted. The estrogen antagonist ICI182780 prevented the increased MnSOD expression and also the changes in cell growth and stress resistance, indicating that these effects are mediated by estrogen receptors (ER). The absence of effects of resveratrol or coumestrol, but not genistein, in ERβ-null cells further indicated that this ER in particular is important in mediating these effects. Thus, an ER-mediated induction of MnSOD expression appears to underlie the growth inhibitory and cytoprotective activities of multiple phytoestrogens.

Topics: Animals; Cell Cycle; Cell Line; Cell Proliferation; Coumestrol; Cytoprotection; Estradiol; Fulvestrant; Genistein; Isoflavones; Kaempferols; Mice; Myoblasts; Phytoestrogens; Receptors, Estrogen; Resveratrol; Stilbenes; Stress, Physiological; Superoxide Dismutase

The naringinase-treated methanol extract of Sophora japonica L. (Fabaceae) seeds showed potent estrogen agonist activity. Through bioassay-guided isolation of the main active constituents from the naringinase-treated methanol extract of S. japonica, the aglycones genistein and kaempferol were found to be the main phytoestrogens in the naringinase-treated extract. In addition, kaempferol was nearly equipotent to genistein as an estrogen agonist. Concerning the compounds isolated from the untreated methanol extract, sophoricoside showed weak estrogenic activity on ERbeta only.

Topics: Benzopyrans; beta-Glucosidase; Digestion; Drug Discovery; Egypt; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Genistein; Kaempferols; Molecular Structure; Multienzyme Complexes; Osmolar Concentration; Phytoestrogens; Phytotherapy; Plant Extracts; Seeds; Sophora; Spectrometry, Mass, Electrospray Ionization; Two-Hybrid System Techniques; Yeasts

Kaempferol, one of the phytoestrogens, is found in berries and Brassica and Allium species and is known to have antioxidative and anti-inflammatory properties. In the present study, we examined the molecular mechanisms underlying the anti-inflammation effect of kaempferol in an aged animal model. To examine the effect of kaempferol in aged Sprague-Dawley rats, kaempferol was fed at 2 or 4 mg/kg/day for 10 days. The data show that kaempferol exhibited the ability to maintain redox balance. Kaempferol suppressed nuclear factor-kappaB (NF-kappaB) activation and expression of its target genes cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and regulated upon activation, and normal T-cell expressed and secreted in aged rat kidney and in tert-butylhydroperoxide-induced YPEN-1 cells. Furthermore, kaempferol suppressed the increase of the pro-inflammatory NF-kappaB cascade through modulation of nuclear factor-inducing kinase (NIK)/IkappaB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged rat kidney. Based on these results, we concluded that anti-oxidative kaempferol suppressed the activation of inflammatory NF-kappaB transcription factor through NIK/IKK and MAPKs in aged rat kidney.

Topics: Aging; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Chemokine CCL2; Kaempferols; Kidney; Male; Mitogen-Activated Protein Kinases; Models, Animal; NF-kappa B; Phytoestrogens; Plant Extracts; Rats; Rats, Sprague-Dawley; T-Lymphocytes; tert-Butylhydroperoxide

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on E2 concentration (< or = 10(-12) M). Kaempferol (10(-5) M) also caused antiproliferative effect on MCF-7 cell in the presence of E2 (10(-11) M) and restored to the addition of excess E2 (10(-7) M), which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at 10(-4) M, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected (10(-5) M), kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess E2 (10(-7) M) indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by E2, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Female; Gene Expression Regulation; Humans; Kaempferols; Luciferases; Phytoestrogens; Receptors, Estrogen; Response Elements; RNA, Messenger; Transfection; Trefoil Factor-1; Tumor Stem Cell Assay; Tumor Suppressor Proteins; Vitellogenins

A high-performance capillary electrophoresis with electrochemical detection (CE-ED) method has been developed for the determination of phytoestrogens from the pericarps and seeds of Sophora japonica L. in this work. Genistin, genistein, rutin, kaempferol and quercetin are important bioactive constituents in these plants. The effects of several factors such as the acidity and concentration of running buffer, the separation voltage, the applied potential and the injection time on the CE-ED procedure were investigated. Under the optimum conditions, the five analytes could be well separated within 18 min in a 75 cm length capillary (i.d. 25 microm) at the separation voltage of 16 kV in a 50 mmol L(-1) borax running buffer (pH 9.0). A 300 microm diameter carbon disk electrode was used as the working electrode positioned carefully opposite the outlet of the capillary in a wall-jet configuration at the potential of +950 mV (vs SCE). Detection limits (S/N = 3) ranged from 1.1 x 10(-7) to 2.8 x 10(-7) g mL(-1) for all fi ve analytes. This method was successfully used to analyse dried Flos sophorae immaturus, pericarps and seeds of dried Fructus sophorae after a relatively simple extraction procedure, and the assay results were satisfactory.

Topics: Electrochemistry; Electrophoresis, Capillary; Genistein; Hydrogen-Ion Concentration; Isoflavones; Kaempferols; Phytoestrogens; Quercetin; Reproducibility of Results; Rutin; Seeds; Sensitivity and Specificity; Sophora

Although many dietary studies have focused on breast cancer risk, few have examined dietary influence on tumor characteristics such as estrogen receptor (ER) status. Because phytoestrogens may modulate hormone levels and ER expression, we analyzed ER status and phytoestrogen intake in a case-case study of 124 premenopausal breast cancer patients. We assessed intake with a food-frequency questionnaire and obtained ER status from medical records. Rather than focusing on risk, we evaluated whether low intakes were more strongly associated with ER-negative tumors than with ER-positive disease. In logistic regression adjusting for potential confounders, threefold greater risks of ER-negative tumors relative to ER-positive tumors were associated with low intake of the isoflavones genistein (odds ratio, OR=3.50; 95% confidence interval, CI=1.43-8.58) and daidzein (OR=3.10; 95% CI=1.31-7.30). Low intake of the flavonoid kaempferol (OR=0.36; 95% CI=0.16-0.83), the trace element boron (OR=0.33; 95% CI=0.13-0.83), and the phytosterol beta-sitosterol (OR=0.42; 95% CI=0.18-0.98) were associated with decreased risk of ER-negative tumors relative to ER-positive disease. Other phytoestrogens were not significantly associated with ER status. Thus, in premenopausal patients, some phytoestrogens may affect breast carcinogenesis by influencing ER status. Such findings suggest new directions for mechanistic research on dietary factors in breast carcinogenesis that may have relevance for prevention and clinical treatment.

Topics: Adult; Anticarcinogenic Agents; Boron; Breast Neoplasms; Diet; Female; Genistein; Humans; Hypolipidemic Agents; Isoflavones; Kaempferols; Middle Aged; Nutritional Status; Odds Ratio; Phytoestrogens; Premenopause; Receptors, Estrogen; Risk Factors; Sitosterols; Surveys and Questionnaires

Reactive oxygen species (ROS) are produced by a wide variety of exogenous chemicals and metabolic processes and cause a broad spectrum of damage to biological systems. As a consequence, ROS react with DNA, among many other biological targets, disrupting its structure and functionality. Estrogen-like compounds mediate DNA damage by ROS generation, implying that their effects can be modulated by antioxidants such as catalase, superoxide dismutase, and vitamin C. We examined DNA damage in human lymphocytes and sperm after treatment with four estrogen-like compounds (beta-estradiol, diethylstilbestrol, daidzein, and genistein) and its modulation by flavonoids (quercetin and kaempferol) using the Comet assay. The results indicated that quercetin and kaempferol reduced the DNA damage produced in sperm and lymphocytes by the four estrogenic compounds. The flavonoids also reduced the DNA damage induced by hydrogen peroxide, which was used as a positive control. Our results demonstrate that the antioxidant properties of flavonoids can protect the integrity of human sperm and lymphocyte DNA from ROS induced by estrogenic compounds.

Topics: Antineoplastic Agents; Antioxidants; Carcinogens; Diethylstilbestrol; DNA Damage; Estradiol; Genistein; Humans; Isoflavones; Kaempferols; Lymphocytes; Male; Phytoestrogens; Quercetin; Reactive Oxygen Species; Spermatozoa

The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay is a widely used screening method to measure cell viability and proliferation. When testing the effects of kaempferol on breast cancer cell number (crystal violet staining) and viability (MTT tetrazolium assay) conflicting results were obtained. Cell number decreased but MTT formazan formation increased, suggesting a direct interaction of kaempferol with the MTT tetrazolium reduction. Direct reductive potential was observed in a cell-free system for the presumptive phytoestrogens kaempferol and resveratrol, and extracts of Hypericum perforatum L. and Cimicifuga racemosa L. All agents led to instantaneous dark blue formazan formation in the absence of cells. Additionally, antioxidants such as ascorbic acid, vitamin E and N-acetylcysteine interfered with the MTT tetrazolium assay. When MCF7 and HS578 cells treated with kaempferol were washed before addition of MTT tetrazolium, the direct reduction of dye was reduced significantly. These results indicate that the MTT tetrazolium assay may lead to false positive results when testing natural compounds with intrinsic reductive potential.

Topics: Acetylcysteine; Antioxidants; Ascorbic Acid; Breast Neoplasms; Cell Division; Cell Survival; Drug Interactions; Estrogens, Non-Steroidal; Flavonoids; Humans; Isoflavones; Kaempferols; Phytoestrogens; Plant Extracts; Plant Preparations; Plants; Quercetin; Resveratrol; Stilbenes; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured; Vitamin E

Amyloid beta protein (Abeta) elicits a toxic effect on neurons in vitro and in vivo. In present study we attempt to elucidate the mechanism by which Abeta confers its neurotoxicity. The neuroprotective effects of phytoestrogens on Abeta-mediated toxicity were also investigated. Cortical neurons treated with 5 microm Abeta-(25-35) for 40 h decreased the cell viability by 45.5 +/- 4.6% concomitant with the appearance of apoptotic morphology. 50 microm kaempferol and apigenin decreased the Abeta-induced cell death by 81.5 +/- 9.4% and 49.2 +/- 9.9%, respectively. Abeta increased the activity of caspase 3 by 10.6-fold and to a lesser extent for caspase 2, 8, and 9. The Abeta-induced activation of caspase 3 and release of cytochrome c showed a biphasic pattern. Apigenin abrogated Abeta-induced cytochrome c release, and the activation of caspase cascade. Kaempferol showed a similar effect but to a less extent. Kaempferol was also capable of eliminating Abeta-induced accumulation of reactive oxygen species. These two events accounted for the remarkable effect of kaempferol on neuroprotection. Quercetin and probucol did not affect the Abeta-mediated neurotoxicity. However, they potentiated the protective effect of apigenin. Therefore, these results demonstrate that Abeta elicited activation of caspase cascades and reactive oxygen species accumulation, thereby causing neuronal death. The blockade of caspase activation conferred the major neuroprotective effect of phytoestrogens. The antioxidative activity of phytoestrogens also modulated their neuroprotective effects on Abeta-mediated toxicity.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Apigenin; Apoptosis; Caspase Inhibitors; Caspases; Cell Survival; Cells, Cultured; Cerebral Cortex; Cysteine Proteinase Inhibitors; Cytochrome c Group; Estrogens, Non-Steroidal; Flavonoids; Isoflavones; Kaempferols; Models, Biological; Neurons; Neuroprotective Agents; Phytoestrogens; Plant Preparations; Quercetin; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Experimental and epidemiologic studies support the view that soyfoods prevent cancer as well as diseases and symptoms associated with estrogen deficiency. Recent research suggests that the isoflavonoid genistein, a phytoestrogen found in abundance in soyfoods, may be one of the principal molecular components responsible for these health benefits. In this study we investigated the effects of a broad physiologically relevant concentration range of genistein on estrogen receptor (ER) binding, induction of the estrogen-regulated antigen pS2, and cell proliferation rate in ER(+) and ER(-) human breast cancer cells grown in vitro. Dose response to genistein was compared with that of estradiol, tamoxifen, and several other structurally similar iso- and bioflavonoids (e.g., equol, kaempferol, and quercetin). Our results revealed that genistein has potent estrogen agonist and cell growth-inhibitory actions over a physiologically achievable concentration range (10 nM-20 microM). Other flavonoids over the same concentration range were good estrogen agonists and poor cell growth inhibitors (equol) or poor estrogen agonists and potent growth inhibitors (kaempferol and quercetin). The growth-inhibitory actions of flavonoids were distinctly different from those of triphenyl antiestrogens like tamoxifen. In summary, our results reveal that genistein is unique among the flavonoids tested, in that it has potent estrogen agonist and cell growth-inhibitory actions over a physiologically relevant concentration range.

Topics: Anticarcinogenic Agents; Breast; Breast Neoplasms; Cell Division; Chromans; DNA, Neoplasm; Dose-Response Relationship, Drug; Epithelial Cells; Epithelium; Equol; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Humans; Isoflavones; Kaempferols; Phytoestrogens; Plant Preparations; Protein Binding; Quercetin; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured