genistein and Breast-Neoplasms

Estrogen governs the regulations of various pathological and physiological actions throughout the body in both males and females. Generally, 17β-estradiol an endogenous estrogen is responsible for different health problems in pre and postmenopausal women. The major activities of endogenous estrogen are executed by nuclear estrogen receptors (ERs) ERα and ERβ while non-genomic cytoplasmic pathways also govern cell growth and apoptosis. Estrogen accomplished a fundamental role in the formation and progression of breast cancer. In this review, we have hyphenated different studies regarding ERs and a thorough and detailed study of estrogen receptors is presented. This review highlights different aspects of estrogens ranging from receptor types, their isoforms, structures, signaling pathways of ERα, ERβ and GPER along with their crystal structures, pathological roles of ER, ER ligands, and therapeutic strategies to overcome the resistance.

Topics: Breast Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Ligands; Male; Receptors, Estrogen

Postmenopausal women are increasingly using botanicals for menopausal symptom relief due to the increased breast cancer risk associated with traditional estrogen therapy. The deleterious effects of estrogens are associated with estrogen receptor (ER)α-dependent proliferation, while ERβ activation could enhance safety by opposing ERα effects. Three medicinal licorice species, Glycyrrhiza glabra ( G. glabra), G. uralensis, and G. inflata, were studied for their differential estrogenic efficacy. The data showed higher estrogenic potency for G. inflata in an alkaline phosphatase induction assay in Ishikawa cells (ERα) and an estrogen responsive element (ERE)-luciferase assay in MDA-MB-231/β41 breast cancer cells (ERβ). Bioassay-guided fractionation of G. inflata led to the isolation of 8-prenylapigenin (3). Surprisingly, a commercial batch of 3 was devoid of estrogenic activity. Quality control by MS and qNMR revealed an incorrect compound, 4'- O-methylbroussochalcone B (10), illustrating the importance of both structural and purity verification prior to any biological investigations. Authentic and pure 3 displayed 14-fold preferential ERβ agonist activity. Quantitative analyses revealed that 3 was 33 times more concentrated in G. inflata compared to the other medicinal licorice extracts. These data suggest that standardization of G. inflata to 3 might enhance the safety and efficacy of G. inflata supplements used for postmenopausal women's health.

Topics: Breast Neoplasms; Chalcones; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Flavones; Glycyrrhiza; Humans; Plant Extracts

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; Hydrogen Bonding; Models, Molecular; Neoplasm Proteins; Quantitative Structure-Activity Relationship

A 14-step biomimetic synthetic route to glyceollin I (1.5% overall yield) was developed and deployed to produce the natural enantiomeric form in soy, its unnatural stereoisomer, and a racemic mixture. Enantiomeric excess was assessed by asymmetric NMR shift reagents and chiral HPLC. Antiproliferative effects were measured in human breast, ovarian, and prostate cancer cell lines, with all three chiral forms exhibiting growth inhibition (GI) in the low to mid μM range for all cells. The natural enantiomer, and in some cases the racemate, gave significantly greater GI than the unnatural stereoisomer for estrogen receptor positive (ER(+)) versus ER(-) breast/ovarian cell lines as well as for androgen receptor positive (AR(+)) versus AR(-) prostate cancer cells. Surprisingly, differences between ER(+) and ER(-) cell lines were not altered by media estrogen conditions. These results suggest the antiproliferative mechanism of glyceollin I stereoisomers may be more complicated than strictly ER interactions.

Topics: Antineoplastic Agents; Biomimetics; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Female; Humans; Magnetic Resonance Spectroscopy; Male; Models, Chemical; Ovarian Neoplasms; Prostatic Neoplasms; Pterocarpans; Receptors, Estrogen; Stereoisomerism

Dihydro-resveratrol (dihydro-R), a prominent polyphenol component of red wine, has a profound proliferative effect on hormone-sensitive tumor cell lines such as breast cancer cell line MCF7. We found a significant increase in MCF7 tumor cells growth rates in the presence of picomolar concentrations of this compound. The proliferative effect of dihydro-R was not observed in cell lines that do not express hormone receptors (MDA-MB-231, BT-474, and К-562).

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dietary Supplements; Female; Flavonoids; Humans; Neoplasms, Hormone-Dependent; Phenols; Polyphenols; Resveratrol; Stilbenes; Wine

From the rhizomes of Belamcanda chinensis, three new compounds, belalloside A (1), belalloside B (2), and belamphenone (3), along with 13 known compounds, resveratrol (4), iriflophenone (5), irisflorentin (6), tectorigenin (7), irilin D (8), tectoridin (9), iristectorin A (10), iristectorin B (11), hispiduloside, androsin, irigenin, iridin, and jaceoside, have been isolated and characterized. Isolates were evaluated for their cell proliferation stimulatory activity against the MCF-7 and T-47D human breast cancer cell lines. Along with 4, 5, 7, and 9, 3 was shown to stimulate not only MCF-7 but also T-47D human breast cancer cell proliferation.

Topics: Breast Neoplasms; Cell Proliferation; Female; Humans; Iridaceae; Isoflavones; Molecular Structure; Phenols; Plants, Medicinal; Resveratrol; Rhizome; Stilbenes; Thailand; Tumor Cells, Cultured

Chemical investigation of a soybean phytochemical concentrate resulted in the isolation and identification of two new isoflavanones, dihydrodaidzin (1) and dihydrogenistin (2), a new isoflavone, 2' ',6' '-O-diacetyloninin (3), and two new triterpenoid saponins (13 and 14). Nine known isoflavonoids (4-12) and three known saponins (15-17) were also identified. Structures of the new compounds were established by a combination of extensive NMR (DEPT, DQF-COSY, HMBC, HMQC, and ROESY) studies and chemical degradation. Cytotoxic activities (ED(50)) of various extracts and selected isoflavonoids and saponins were measured against human stomach carcinoma (Hs 740.T, Hs 756 T), breast adenocarcinoma (Hs 578 T, Hs 742.T), and prostate carcinoma (DU 145, LNCaP-FGC) cell lines. Isoflavonoids 3 and 5 were more active than 1 and 2 versus at least one of the three cell lines examined, indicating the importance of the 2,3-double bond in cytotoxicity. Saponins 13, 14, and 15 were slightly more active than saponins 16 and 17, indicating that sugar attachments at position-22 enhance cytotoxic activity.

Topics: Breast Neoplasms; Drug Screening Assays, Antitumor; Female; Glycine max; Humans; Hydrolysis; Inhibitory Concentration 50; Isoflavones; Male; Nuclear Magnetic Resonance, Biomolecular; Plants, Medicinal; Prostatic Neoplasms; Saponins; Stereoisomerism; Stomach Neoplasms; Structure-Activity Relationship; Triterpenes; Tumor Cells, Cultured

In the course of our search for new antitumor agents in breast cancer, novel amino-substituted flavone derivatives were synthesized and examined for antitumor activities. Among them, 5,4'-diaminoflavone and some of its congeners showed remarkable antiproliferative activity against the estrogen receptor (ER)-positive and estrogen-responsive human breast cancer cell line MCF-7. The activity was observed irrespective of the presence or absence of estrogen. The 5-aminoflavone derivatives (5-AFs) are not classical anti-estrogens because they did not compete with [3H]estradiol to bind the estrogen receptor. Moreover, 5-AFs showed antitumor activity highly selective to the ER-positive breast cancer cell line, and they showed no effects against the ER-negative human cancer cell lines HeLa S3, WiDr, and MDA-MB-453. Although the mechanism of their selective antitumor activity to ER-positive breast cancer cells is unclear, 5-AFs are expected to be a new type of antitumor agents in breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Estradiol; Female; Flavonoids; HeLa Cells; Humans; Receptors, Estrogen; Structure-Activity Relationship; Tumor Cells, Cultured

A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole nucleus involves a Jacobson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120gag-abl tyrosine kinase compared with the parental 3T3 line. Compounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Colonic Neoplasms; ErbB Receptors; Fibroblasts; Genistein; Humans; Hydroxylation; Isoflavones; Mice; Molecular Structure; Protein-Tyrosine Kinases; Quercetin; Structure-Activity Relationship; Thiazoles; Tumor Cells, Cultured