Identification of the Potent Phytoestrogen Glycinol in Elicited Soybean (Glycine max)

Boué, Stephen M.; Tilghman, Syreeta L.; Elliott, Steven; Zimmerman, Michael; Williams, Karin; Payton‐Stewart, Florastina; Miraflor, Allen P.; Howell, Melanie; Shih, Betty Y.; Carter-Wientjes, Carol H.; Segar, Chris; Beckman, Barbara S.; Wiese, Thomas E.; Cleveland, Thomas E.; McLachlan, John A.; Burow, Matthew E.

doi:10.1210/en.2008-1235

Cited by 51 publications

(41 citation statements)

References 47 publications

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“…It is interesting to note that in our previous publication, we investigated a novel isoflavone, glycinol, a precursor to glyceollin that is produced in elicited soy, and we found it to be a potent phytoestrogen (Boue et al, 2009). In the current study, we demonstrate that glyceollin I is the most potent, antiestrogenic isomer of the glyceollin mixture and is distinctly different from its estrogenic precursor glycinol (Boué et al, 2009).…”

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confidence: 49%

“…3 (Banks and Dewick, 1983). Glycinol, which we have shown previously to be estrogenic (Boué et al, 2009), is derived from daidzein via a pterocarpan by cyclization and 6␣-hydroxylation with retention of configuration (Banks and Dewick, 1983;Hagmann et al, 1984). For the synthesis of the glyceollins, glycinol is prenylated to produce glyceollidin I and II, followed by cyclization into the corresponding glyceollins (Zä hringer et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

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Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

Zimmermann

Tilghman

Boué³

et al. 2009

J Pharmacol Exp Ther

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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

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confidence: 49%

Section: Discussionmentioning

confidence: 99%

Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

Zimmermann

Tilghman

Boué³

et al. 2009

J Pharmacol Exp Ther

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“…In Western countries, soy is used as a healthy functional food for postmenopausal women. Many researchers have reported that soybean, isoflavones, glycinol, and soyasaponins exhibit estrogenic activity (Tham et al, 1998;Rowlands et al, 2002;Lehmann et al, 2005;Park et al, 2006;Boué et al, 2009;Cederroth and Nef, 2009). The isoflavones also activate estrogen-responsive genes and regulate the growth of human breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Soyasaponin I by Human Intestinal Microflora and Its Estrogenic and Cytotoxic Effects

Chang¹,

Han²,

Han³

et al. 2009

Biomolecules and Therapeutics

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-Metabolites of Soyasaponin I, a major constituent of soybean, by human intestinal microflora were investigated by LC-MS/MS analysis. We found four peaks, one parental constituent and three metabolites:which was an unknown metabolite, soyasapogenol B 3-β-D-glucuronide. When soyasaponin I was incubated with the human fecal microbial fraction from ten individuals for 48 h, soyasaponin I was metabolized to soyasapogenol B via soyasaponin III and soyasapogenol B 3-β-D-glucuronide or via soyasaponin III alone. Both soyasaponin I and its metabolite soyasapgenol B exhibited estrogenic activity. Soyasaponin I increased the proliferation, mRNA expression of c-fos and pS2, in MCF7 cells more potently than soyasapogenol B. However, soyasapogenol B showed potent cytotoxicity against A549, MCF7, HeLa and HepG2 cells, while soyasaponin I did not. The cytotoxicity of soyasapogenol B may prevent its estrogenic effect from increasing dose-dependently. These findings suggest that orally administered soyasaponin I may be metabolized to soyasapogenol B by intestinal microflora and that soyasapogenol B may express a cytotoxic effect rather than an estrogenic effect.

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“…Soy foods contain bioactive components other than GEN that have been linked to cancer protection (Boué et al 2009;Wang et al 2008;Zhou et al 2002). Lunasin (LUN) is a 43-amino acid peptide component of post-translationally processed 2S albumin, initially identified in soybeans (Galvez and de Lumen 1999) and also present in barley, wheat and other seeds (Jeong et al 2007(Jeong et al , 2010Silva-Sanchez et al 2008).…”

Section: Introductionmentioning

confidence: 99%

The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

Pabona

Dave

et al. 2012

Genes Nutr

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Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature and precise actions of specific bioactive components present in foods with purported health effects. The 43-amino acid peptide lunasin (LUN) is found in soybeans, is bioavailable similar to the isoflavone genistein (GEN), and thus may mediate the beneficial effects of soy food consumption. Here, we evaluated whether LUN displays common and distinct actions from those of GEN in non-malignant (mouse HC11) and malignant (human MCF-7) mammary epithelial cells. In MCF-7 cells, LUN up-regulated tumor suppressor phosphatase and tensin homolog deleted in chromosome ten (PTEN) promoter activity, increased PTEN transcript and protein levels and enhanced nuclear PTEN localization, similar to that shown for GEN in mammary epithelial cells. LUN-induced cellular apoptosis, akin to GEN, was mediated by PTEN, but unlike that for GEN, was p53-independent. LUN promoted E-cadherin and b-catenin nonnuclear localization similar to GEN, but unlike GEN, did not influence the proliferative effects of oncogene Wnt1 on HC11 cells. Further, LUN did not recapitulate GEN inhibitory effects on expansion of the cancer stem-like/ progenitor population in MCF-7 cells. Results suggest the concerted actions of GEN and LUN on cellular apoptosis for potential mammary tumor preventive effects and highlight whole food consumption rather than intake of specific dietary supplements with limited biological effects for greater health benefits.

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Identification of the Potent Phytoestrogen Glycinol in Elicited Soybean (Glycine max)

Cited by 51 publications

References 47 publications

Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

Glyceollin I, a Novel Antiestrogenic Phytoalexin Isolated from Activated Soy

Metabolism of Soyasaponin I by Human Intestinal Microflora and Its Estrogenic and Cytotoxic Effects

The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

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