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United States Department of Agriculture

Agricultural Research Service

Title: Glyceollin I, A Novel Antiestrogenic Phytoalexin Isolated from Activated Soy)

Author
item Zimmermann, M. carla
item Tilghman, Syreeta
item Boue, Stephen
item Salvo, Virgilio
item Elliott, Steven
item Williams, K. y.
item Skripnikova, Elena
item Ashe, Hasina
item Payton-stewart, Florastina
item Vanhoy-rhodes, Lyndsay
item Fonseca, Juan pablo
item Corbitt, Cynthia
item Collins-burow, Bridgette
item Howell, Melanie
item Lacey, Michelle
item Shih, Betty
item Carter-wientjes, Carol
item Cleveland, Thomas
item Mclachlan, John
item Wiese, Thomas
item Beckman, Barbara
item Burow, Matthew

Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer reviewed journal
Publication Acceptance Date: 9/30/2009
Publication Date: 1/4/2010
Citation: Zimmermann, M., Tilghman, S.L., Boue, S.M., Salvo, V.A., Elliott, S., Williams, K., Skripnikova, E.V., Ashe, H., Payton-Stewart, F., Vanhoy-Rhodes, L., Fonseca, J., Corbitt, C., Collins-Burow, B.M., Howell, M.H., Lacey, M., Shih, B.Y., Carter Wientjes, C.H., Cleveland, T.E., Mclachlan, J.A., Wiese, T.E., Beckman, B.S., Burow, M.E. 2010. Glyceollin I, A Novel Antiestrogenic Phytoalexin Isolated from Activated Soy. Journal of Pharmacology and Experimental Therapeutics. 332(1):35-45.

Interpretive Summary: Glyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be a novel antiestrogen which bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. Our previous publications have focused specifically on inhibition of tumor formation and growth by the glyceollin mixture, which contains three glyceollin isomers (I, II and III). Here, we show the glyceollin mixture is also effective as a potential antiestrogenic, therapeutic agent that prevents estrogen-stimulated tumorigenesis and displays a differential pattern of gene expression from tamoxifen. By isolating the individual glyceollin isomers (I, II and III) we have identified the active antiestrogenic component using several assays. We identified glyceollin I as the active component of the combined glyceollin mixture. Molecular modeling of glyceollin I, II and III docking to the estrogen receptor binding cavity demonstrates a unique conformation adopted by glyceollin I, but not isomers II and III. Our results establish a novel inhibition of gene expression and cell proliferation/survival. Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic agent of hormone-dependent tumors.

Technical Abstract: Glyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be a novel antiestrogen which bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. Our previous publications have focused specifically on inhibition of tumor formation and growth by the glyceollin mixture, which contains three glyceollin isomers (I, II and III). Here, we show the glyceollin mixture is also effective as a potential antiestrogenic, therapeutic agent that prevents estrogen-stimulated tumorigenesis and displays a differential pattern of gene expression from tamoxifen. By isolating the individual glyceollin isomers (I, II and III) we have identified the active antiestrogenic component using competition binding assays with human ERa and in an estrogen responsive element-based luciferase reporter assay (ERE-Luc). We identified glyceollin I as the active component of the combined glyceollin mixture. Molecular modeling of glyceollin I, II and III docking to the ERa ligand binding cavity demonstrates a unique Type II antiestrogenic confirmation adopted by glyceollin I, but not isomers II and III. We further compared the effects of glyceollin I to the antiestrogens, 4-hydroxytamoxifen (4-OH-Tam) and ICI 182,780 (fulvestrant), in MCF-7 breast cancer cells and BG-1 ovarian cancer cells on 17ß-estradiol (E2) stimulated expression of progesterone receptor (PgR) and stromal derived factor-1a (SDF-1). Our results establish a novel inhibition of ER-mediated gene expression and cell proliferation/survival. Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic agent of hormone-dependent tumors.

Last Modified: 8/24/2016
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