Antiestrogenic glyceollins suppress human breast and ovarian carcinoma proliferation and tumorigenesis
Inactive Publication Date: 2006-11-02
UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC OF AGRI THE
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[0012] It is a further object of the invention to provide a composition containing glyceollin for preventing or minimizing the development or growth of breast cancer and ovarian cancer.
[0013] It is another object of the invention to provide a method for preventing or minimizing
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Ultimately tumors can develop resistance, and in the case of the antiestroge
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example 1
Soybean Treatment and Harvesting
[0038]Aspergillus sojae (S RRC 1125) cultures were grown at 25° C. in the dark on potato dextrose agar. After 5 days, inoculum was prepared by harvesting conidia (3.4×107 / ml) in 15 ml sterile, distilled H2O. Seeds from commercial soybean variety Asgrow 5902 were surface-sterilized for 3 min in 70% ethanol followed by a quick deionized-H2O rinse and two 2 min rinses in deionized-H2O. Seeds were presoaked in sterile deionized-H2O for 4-5 hr, then chopped for 2 min in a Cuisinart food processor. A. sojae spore suspension (300 μl) was applied to the cut surface of seeds on each tray. All trays were stored at 25° C. in the dark for three days, rinsed with water to remove spores, and oven dried at 40° C. for 24 hrs. Seeds were ground using a Waring blender before extraction.
example 2
Isolation of Glyceollins
[0039] A mixture of Glyceollins I, II, and III were isolated using a procedure developed at the Southern Regional Research Center (ARS, USDA, New Orleans, La.). Soybean seeds (1 kg) were sliced and inoculated with Aspergillus soiae, as in Example 1. After three days, the glyceollins were extracted from the inoculated seeds with methanol (1 liter). The Glyceollins were isolated using preparative scale HPLC using two Waters 25 mm 10 μm particle size μBondapak C18 radial compression column segments combined using an extension tube. HPLC was performed on a Waters 600E System Controller combined with a Waters UV-VIS 996 detector. Elution was carried out at a flow rate of 8.0 ml / min with the following solvent system: A+acetonitrile, B=water; 5% A for 10 min, then 5% A to 90% A in 60 min followed by holding at 90% A for 20 min. The injection volume was 20 ml. The fraction containing the glyceollins was concentrated under vacuum and freeze-dried. The glyceollins wer...
example 3
Cell Culture; In Vitro Colony Assay
[0040] The MCF-7N cell variant is a subclone of MCF-7 cells from the American Type Culture Collection (Manassas, Va.) that was generously provided by Louise Nutter (University of Minnesota, Minneapolis, Minn.) and has been previously described (Graham et al., supra). The BG-1 cell line has been previously described. MCF-7 and BG-1 cells were grown in Dulbecco's modified minimal medium (pH 7.4; Life Technologies, Inc., Grand Island, N.Y.) supplemented with 10% fetal bovine serum (Hyclone, Salt Lake City, Utah). For studies with estrogen, the cells were cultured in medium supplemented with 5% charcoal-stripped fetal bovine serum. The cells were incubated at 37° C. in an atmosphere of 5% CO2 and air.
[0041] MCF-7 cells are plated at 103 / well in 6 well Cluster dishes, and incubated overnight. Cells are cultured and treated in DMEM without phenol red; phenol red interacts with estrogen receptors. Treatment and control plates were incubated at 37° C., 5...
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Abstract
The flavonoid family of phytochemicals, particularly those derived from soy, has received attention regarding their hormonal activity and their effects on human health and disease. The types and amounts of these compounds in soy and other plants are controlled by both constitutive expression and stress-induced biosynthesis. The health benefits of soy may therefore be dependent upon the amounts of the various hormonally active phytochemicals present. We have identified increased biosynthesis of the isoflavonoid phytoalexin compounds, Glyceollins I, II and III, in soy plants grown under stressed conditions (elicited soy), which exhibit marked anti-estrogenic effects on ER function. Here we demonstrate that specific glyceollins, isolated from elicited soy, displayed anti-estrogenic activity, suppressing basal and estrogen stimulated colony formation of ER-positive estrogen dependent breast cancer cells and inhibiting ER-dependent gene expression of progesterone receptor (PgR) and stromal derived factor-1 (SDF1/CXCL12). Examining the effects of glyceollin on in vivo tumor formation/growth we demonstrate the ability of glyceollins to significantly suppress basal and estrogen-stimulated tumor growth of ER-positive MCF-7 breast and BG-1 ovarian carcinoma cells in ovariectomized female nude mice. We further demonstrate that the effects of glyceollins on suppression of tumor growth correlate with inhibition of estrogen stimulated PgR expression. In contrast to the uterotropic activity of tamoxifen the glyceollins displayed no uterine agonist activity. The Glyceollin (I-III) compounds may represent an important component of the health effects of soy as well as represent novel anti-estrogens useful in the prevention or treatment of breast and ovarian carcinoma.
Description
BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to increased biosynthesis and isolation of the isoflavonoid phytoalexin compounds, Glyceollins I, III and II, in soy plants grown under stressed conditions, a composition containing said glyceollin(s), a selective estrogen receptor modulator, and a method of treating and preventing breast and ovarian carcinoma while inhibiting selective estrogen receptor modulator-induced uterotrophic effects. [0003] 2. Description of the Relevant Art [0004] During endocrine therapy, the antiestrogen tamoxifen has been shown to prevent pre- and postmenopausal breast cancer and to be a beneficial adjuvant therapy for women with estrogen receptor-positive tumors. Ultimately tumors can develop resistance, and in the case of the antiestrogen tamoxifen, tamoxifen can increase the risk of endometrial cancer (Brown, K. 2002. Expert Opin. Drug Saf. 1: 253-267). Consequently, efforts have been made to develop ne...
Claims
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IPC IPC(8): A61K38/16A61K36/48A61K31/353
CPCA61K36/48A61P35/00
Inventor CLEVELAND, THOMAS E.BOUE, STEPHEN M.BUROW, MATTHEW E.MCLACHLAN, JOHN A.
Owner UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC OF AGRI THE
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