Dataset Information

Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.

ABSTRACT: Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.

SUBMITTER: Jiang Q

PROVIDER: S-EPMC2956131 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.

Jiang Quan Q Payton-Stewart Florastina F Elliott Steven S Driver Jennifer J Rhodes Lyndsay V LV Zhang Qiang Q Zheng Shilong S Bhatnagar Deepak D Boue Stephen M SM Collins-Burow Bridgette M BM Sridhar Jayalakshmi J Stevens Cheryl C McLachlan John A JA Wiese Thomas E TE Burow Matthew E ME Wang Guangdi G

Journal of medicinal chemistry 20100801 16

Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and ...[more]

PMID: 20669983

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Project description:The fluorescence-based multi-analyte chip platform for the analysis of estrogenic and anti-estrogenic substances is a new in vitro tool for the high throughput screening of environmental samples. In contrast to existing tools, the chip investigates the complex action of xenoestrogens in a human cell model by characterizing protein expression. It allows for the quantification of 10 proteins secreted by MCF-7 cells, representing various biological and pathological endpoints of endocrine action and distinguishing between estrogen- and anti-estrogen-dependent secretion of proteins. Distinct protein secretion patterns of the cancer cell line after exposure to known estrogen receptor agonists ß-estradiol, bisphenol A, genistein, and nonylphenol as well as antagonists fulvestrant and tamoxifen demonstrate the potential of the chip. Stimulation of cells with Interleukin-1ß shifts concentrations of low abundant biomarkers towards the working range of the chip. In the non-stimulated cell culture, Matrix Metalloproteinase 9 (MMP-9) and Vascular Endothelial Growth Factor (VEGF) show differences upon treatment with antagonists and agonists of the estrogen receptor. In stimulated MCF-7 cells challenged with receptor agonists secretion of Monocyte Chemoattractant Protein (MCP-1), Interleukin-6 (IL-6), Rantes, and Interleukin-8 (IL-8) significantly decreases. In parallel, the proliferating effect of endocrine-disrupting substances in MCF-7 cells is assessed in a proliferation assay based on resazurin. Using ethanol as a solvent for test substances increases the background of proliferation and secretion experiments, while using dimethyl sulfoxide (DMSO) does not show any adverse effects. The role of the selected biomarkers in different physiological processes such as cell development, reproduction, cancer, and metabolic syndrome makes the chip an excellent tool for either indicating endocrine-disrupting effects in food and environmental samples, or for screening the effect of xenoestrogens on a cellular and molecular level.

Project description:We have previously demonstrated that endoxifen is the most important tamoxifen metabolite responsible for eliciting the anti-estrogenic effects of this drug in breast cancer cells expressing estrogen receptor-alpha (ER?). However, the relevance of ER? in mediating endoxifen action has yet to be explored. Here, we characterize the molecular actions of endoxifen in breast cancer cells expressing ER? and examine its effectiveness as an anti-estrogenic agent in these cell lines.MCF7, Hs578T and U2OS cells were stably transfected with full-length ER?. ER? protein stability, dimer formation with ER? and expression of known ER target genes were characterized following endoxifen exposure. The ability of various endoxifen concentrations to block estrogen-induced proliferation of MCF7 parental and ER?-expressing cells was determined. The global gene expression profiles of these two cell lines was monitored following estrogen and endoxifen exposure and biological pathway analysis of these data sets was conducted to identify altered cellular processes.Our data demonstrate that endoxifen stabilizes ER? protein, unlike its targeted degradation of ER?, and induces ER?/ER? heterodimerization in a concentration dependent manner. Endoxifen is also shown to be a more potent inhibitor of estrogen target genes when ER? is expressed. Additionally, low concentrations of endoxifen observed in tamoxifen treated patients with deficient CYP2D6 activity (20 to 40 nM) markedly inhibit estrogen-induced cell proliferation rates in the presence of ER?, whereas much higher endoxifen concentrations are needed when ER? is absent. Microarray analyses reveal substantial differences in the global gene expression profiles induced by endoxifen at low concentrations (40 nM) when comparing MCF7 cells which express ER? to those that do not. These profiles implicate pathways related to cell proliferation and apoptosis in mediating endoxifen effectiveness at these lower concentrations.Taken together, these data demonstrate that the presence of ER? enhances the sensitivity of breast cancer cells to the anti-estrogenic effects of endoxifen likely through the molecular actions of ER?/? heterodimers. These findings underscore the need to further elucidate the role of ER? in the biology and treatment of breast cancer and suggest that the importance of pharmacologic variation in endoxifen concentrations may differ according to ER? expression.

Dataset Information

Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.

Publications

Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.

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