Glyceollin I, a novel antiestrogenic phytoalexin isolated from activated soy.
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 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 by using competition binding assays with human ERalpha 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 ERalpha 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 17beta-estradiol-stimulated expression of progesterone receptor and stromal derived factor-1alpha. 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 hormone-dependent tumors.
Zimmermann
M Carla
MC
Department of Pharmacology, Tulane University, New Orleans, Louisiana 70112, USA.
Tilghman
Syreeta L
SL
Boué
Stephen M
SM
Salvo
Virgilio A
VA
Elliott
Steven
S
Williams
K Y
KY
Skripnikova
Elena V
EV
Ashe
Hasina
H
Payton-Stewart
Florastina
F
Vanhoy-Rhodes
Lyndsay
L
Fonseca
Juan Pablo
JP
Corbitt
Cynthia
C
Collins-Burow
Bridgette M
BM
Howell
Melanie H
MH
Lacey
Michelle
M
Shih
Betty Y
BY
Carter-Wientjes
Carol
C
Cleveland
Thomas E
TE
McLachlan
John A
JA
Wiese
Thomas E
TE
Beckman
Barbara S
BS
Burow
Matthew E
ME
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D036343:Pterocarpans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D012717:Sesquiterpenes; D013025:Glycine max / Q000737:chemistry*; D013237:Stereoisomerism; D013629:Tamoxifen / Q000494:pharmacology; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000094162:Phytoalexins
D016588:Anticarcinogenic Agents; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D036343:Pterocarpans; D012717:Sesquiterpenes; D013729:Terpenes; D013629:Tamoxifen; C017343:glyceollin; D000094162:Phytoalexins