Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

Abstract

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.Breast cancer accounts for 25% of all female cancers, making it the most common cancer in women in the western world (Greenlee et al., 2000Lester, 2007 Ali and Coombs, 2002). For patients with hormone receptor-positive breast cancer, several promising endocrine agents are currently available with promising results. Therapies have been developed to reduce estrogen levels or to block signaling through estrogen receptors (ER) (Pink and Jordan, 1996;Howell, 2006). These agents include tamoxifen, a selective estrogen

Risks and benefits related to alimentary exposure to xenoestrogens

“…Then, these three components were purified and investigated separately: the active component of this mixture resulted to be glyceollin I, with an IC 50 value of 1.68 µM against ERα, whereas the IC 50 values of glyceollins II and III were 6.57 and >10 µM, respectively. Thus, this study demonstrated that glyceollin I acts as a potent ERs antagonist (Zimmerman et al, 2006). Moreover, further studies attributed the antiestrogenic activity of glyceollin I to the natural (−)-glyceollin I enantiomer, which was compared to those of the racemate and of the unnatural (+) enantiomer (Payton-Stewart et al, 2010).…”

Beneficial Effects of Pterocarpan-High Soybean Leaf Extract on Metabolic Syndrome in Overweight and Obese Korean Subjects: Randomized Controlled Trial

“…In particular, pterocarpans such as coumesterol, glyceofuran, glyceollin III suppressed the oxidation of low-density lipoprotein (LDL) [20], and have been reported to have cancer prevention and anti-inflammatory effects [21,22,23]. In addition, glyceollins (I–III), prenylated pterocarpan have known antiestrogenic effects in vivo [24,25]. In a previous study, soy leaf exhibited non-HDL-cholesterol lowering effects in hamsters [26]—as well as ethyl acetate extracts of soybean leaves, including pterocarpan—ameliorated the insulin sensitivity and improved the plasma glucose levels in high-fat diet (HFD)-induced type 2 diabetic mice [27].…”

Glyceollin Effects on MRP2 and BCRP in Caco-2 Cells, and Implications for Metabolic and Transport Interactions

“…Initial studies of glyceollins' biological effects indicated that they were estrogen receptor antagonists (6), exhibited anti-proliferative effects in estrogen-dependent breast cancer cells (7), and inhibited cell proliferation in mouse xenograft breast cancer models (8). More recently, glyceollins demonstrated improvement in glucose homeostasis in response to a glucose challenge in a prediabetic rat model of type 2 diabetes (9) and lowered cholesterol in a hamster model of human cholesterol metabolism (10).…”