Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 332; no. 1; pp. 35 - 45
• Main Authors: Zimmermann, M. Carla, Tilghman, Syreeta L, Boue, Stephen M, Salvo, Virgilio A, Elliott, Steven, Williams, K.Y, Skripnikova, Elena V, Ashe, Hasina, Payton-Stewart, Florastina, Vanhoy-Rhodes, Lyndsay, Fonseca, Juan Pablo, Corbitt, Cynthia, Collins-Burow, Bridgette M, Howell, Melanie H, Lacey, Michelle, Shih, Betty Y, Carter-Wientjes, Carol, Cleveland, Thomas E, McLachlan, John A, Wiese, Thomas E, Beckman, Barbara S, Burow, Matthew E
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 2010; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: activated soy; Animals; anticarcinogenic activity; Anticarcinogenic Agents - chemistry; Anticarcinogenic Agents - isolation & purification; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; antiestrogens; Aspergillus; Aspergillus sojae; binding capacity; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Endocrine and Diabetes; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - biosynthesis; Estrogen Receptor alpha - genetics; Estrogen Receptor Modulators - chemistry; Estrogen Receptor Modulators - isolation & purification; Estrogen Receptor Modulators - pharmacology; Estrogen Receptor Modulators - therapeutic use; estrogens; Female; fermentation; glyceollin I; glyceollins; Glycine max - chemistry; hormone receptors; Humans; medicinal properties; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Phytoalexins; Pterocarpans - chemistry; Pterocarpans - isolation & purification; Pterocarpans - pharmacology; Pterocarpans - therapeutic use; Sesquiterpenes; soybeans; Stereoisomerism; Tamoxifen - pharmacology; Terpenes - chemistry; Terpenes - isolation & purification; Terpenes - pharmacology; Terpenes - therapeutic use; transcription factors; Transcription, Genetic - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.160382

Glyceollins, a group of novel phytoalexins isolated from activated soy, have recently been demonstrated to be novel antiestrogens that 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 estrogenstimulated 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 by using competition binding assays with human ER and in an estrogen-responsive element-based luciferase reporter assay. We identified glyceollin I as the active component of the combined glyceollin mixture. Ligand-receptor modeling (docking) of glyceollin I, II, and III within the ER 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 and ICI 182,780 (fulvestrant), in MCF-7 breast cancer cells and BG-1 ovarian cancer cells on 17 - estradiol-stimulated expression of progesterone receptor and stromal derived factor-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 for hormonedependent tumors.