Antiestrogenic glyceollins suppress human breast and ovarian carcinoma proliferation and tumorigenesis

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.

1 . A pharmaceutical composition for the treatment of breast cancer and ovarian cancer, wherein said composition comprises isolated glyceollin in an amount effective for the therapeutic treatment of breast cancer and ovarian cancer.  
   
   
       2 . The composition of  claim 1  wherein glyceollin is isolated from elicited soy.  
   
   
       3 . The composition of  claim 2  wherein said glyceollin isolated from elicited soy is Glyceollin I, II, and III.  
   
   
       4 . The composition of  claim 1  in which in the effective therapeutic amount of said glyceollin in said composition is selected on the basis of a treatment for breast cancer.  
   
   
       5 . The composition of  claim 4  wherein said therapeutic amount of said glyceollin in said composition is 100 nM to 50 μM.  
   
   
       6 . The composition of  claim 1  in which in the effective therapeutic amount of said glyceollin in said composition is selected on the basis of a treatment for ovarian cancer.  
   
   
       7 . The composition of  claim 4  wherein said therapeutic amount of said glyceollin in said composition is 100 nM to 50 μM.  
   
   
       8 . A composition for preventing, minimizing, or reversing the development or growth of breast cancer or ovarian cancer in a female individual comprising glyceollin, wherein said glyceollin is present in said composition in an amount effective to prevent, minimize, or reverse the development or growth of breast cancer or ovarian cancer in a the individual upon adminstration to said individual.  
   
   
       9 . The composition of  claim 8  wherein said glyceollin is administered in an amount of 1 mg/kg/individual to 50 mg/kg/individual.  
   
   
       10 . The composition of  claim 8  wherein said glyceollin is present in an amount sufficient to augment prevention or minimization of development or growth of breast cancer or ovarian cancer provided by SERMs upon administration of said composition to a female individual.  
   
   
       11 . The composition of  claim 10 , wherein said glyceollin is present in said composition in an amount effective to prevent or minimize uterotrophic effects induced by a SERM in said individual.  
   
   
       12 . The composition of  claim 1  in which said composition is in a form of a product for oral delivery, said product form being selected from a group consisting of a concentrate, dried powder, liquid, capsule, pellet, pill, and a food supplement including health bars.  
   
   
       13 . The composition of  claim 1  in which said composition is in a form of a product for parenteral administration including intravenous, intradermal, intramuscular, and subcutaneous administration.  
   
   
       14 . The composition of  claim 1  further comprising carriers, binders, diluents, and excipients.  
   
   
       15 . A method of inhibiting tumor growth comprising contacting a tumor with a composition comprising glyceollin and determining that growth of said tumor has been inhibited.  
   
   
       16 . A method of preventing or treating cancer or tumor growth in a female individual comprising administering to the individual a composition comprising glyceollin and determining the development or growth of breast cancer or ovarian cancer has been prevented, minimized, or reversed.  
   
   
       17 . A method of inhibiting uterotrophic effects in a female individual comprising administering to the individual a composition comprising glyceollin and determining that uterotrophic effects have been inhibited.  
   
   
       18 . A method of preventing uterotrophic effects in a female individual comprising administering to the individual a composition comprising glyceollin and determining that uterotrophic effects have been prevented.