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.
Department of Pharmacology, Tulane University, New Orleans, Louisiana 70112, USA.
M Carla
MC
Zimmermann
Syreeta L
SL
Tilghman
Stephen M
SM
Boué
Virgilio A
VA
Salvo
Steven
S
Elliott
K Y
KY
Williams
Elena V
EV
Skripnikova
Hasina
H
Ashe
Florastina
F
Payton-Stewart
Lyndsay
L
Vanhoy-Rhodes
Juan Pablo
JP
Fonseca
Cynthia
C
Corbitt
Bridgette M
BM
Collins-Burow
Melanie H
MH
Howell
Michelle
M
Lacey
Betty Y
BY
Shih
Carol
C
Carter-Wientjes
Thomas E
TE
Cleveland
John A
JA
McLachlan
Thomas E
TE
Wiese
Barbara S
BS
Beckman
Matthew E
ME
Burow
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