Estrogenic Activity of Isoflavonoids fromOnobrychis ebenoides

Abstract

Fractionation of the neutral extract of Onobrychis ebenoides (Leguminosae) yielded a new isoflavone, named ebenosin (1), in addition to the known ones, afrormosin (2), formononetin (3) and daidzein (4). Although the relative binding affinities of 1 - 4 for estrogen receptor alpha (ERalpha) were nearly comparable and matched those of 1-3 for ERbeta, that of 4 for the latter receptor was significantly higher than any of the other. Compounds 1 - 4 induced cell proliferation and gene expression in breast and endometrial cancer cells in an ER-dependent manner. Nonetheless, the rank order of induction potencies ( 4 > 3 >or= 2 >or= 1) matched better that of affinities for ERbeta ( 4 > 3 >or= 2 >or= 1) rather than ERalpha ( 4 >or= 3 >or= 2 >or= 1). While the antiestrogen ICI 182,780 could inhibit the induction of proliferation of ER-positive breast cancer cells by 1-4, it could not prevent 1 from exhibiting significant ER-independent cytotoxicity at 10 microM. By contrast, 1 was much less cytotoxic and only weakly estrogenic for ER-positive endometrial adenocarcinoma cells. In conclusion, our data suggest that the C-8 isoprenyl substituent of 1 renders it cytotoxic and/or estrogenic in a cell-dependent manner.

A systematic review on biological activities of prenylated flavonoids

“…Geranylation induced cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells (Cho et al, 2012). By studying the isoprenylated flavonoids extracted from Onobrychis ebenoides, the results suggested that the isoprenyl substituent at C-8 rendered cytotoxic and/or estrogenic in a cell-dependent manner (Halabalaki et al, 2006). The presence of prenyl, geranyl or farnesyl group at position 6 of the A ring of baicalein derivatives would affect their cytotoxic activities by modulating apoptosisrelated proteins such as Bax and Bcl-2.…”

New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription

“…Estradiol is known to fully induce the proliferation of MCF-7 cells at concentrations P0.1 nM and 1 lM ICI172,780 to fully inhibit the hormonal effect. 40 Most of the derivatives, including the topmost neuroprotective 2, 4 and 6, could not stimulate cell proliferation or interfere with stimulation of cell proliferation by estradiol nor affect cell viability in the absence or presence of estradiol (not shown). These data are in accordance with 2, 4 and 6 being unable to interfere with ERa signaling to gene expression in MCF-7:D5L cells at concentrations up to 1 lM (Table 3, columns 2 and 3).…”

“…40 Briefly, we determined the concentrations of estradiol, ICI182,780, resveratrol and 1-11 that inhibited the binding of the fluorescent estrogen ES2 (Invitrogen) to the isolated recombinant human ERa or ERb (Invitrogen) by 50% (IC 50 ), and used them to derive the RBA values of Table 2 as described in the legend to the table.…”

“…Twenty-four hours after plating, cells were exposed to test compounds in the absence or presence of 0.1 nM estradiol or 1 lM ICI182,780 for 72 h and compound effects on AlkP activity were assessed as already described, 40 with minor modifications. Briefly, the cells were washed with PBS twice, placed at À80°C for at least 1 h, thawed at room temperature for 5-10 min, and then transferred on ice.…”

The estrogen receptor and polyphenols: molecular simulation studies of their interactions, a review

“…The group consists of well known isoflavones like Genistein, Coumestrol (COUM), Daidzein (DAI) BiochaninA (BIOC), Formononetin (FORM), Deoxybenzoins (intermediates in the synthesis of isoflavones) like Ononetine (DB1), along with several synthetic analogues (compounds DB2-DB11), Benzofurans (compounds BF1-BF4) and steroidal androgens Androstenediol (A7830) and Androstanediol (A1220). Binding of these compounds to ERα and ERβ was studied along with their biological activity as assessed on the basis of their effect on cell proliferation and gene expression (Fokialakis et al 2004;Halabalaki et al 2005;Katsanou et al 2005) Compared to the natural hormone E2 they exhibit, as expected for phytoestrogens, weak affinity for both ERαand ERβ (Table 1) with the exception of Genistein and Coumestrol which are known to be selective towards ERβ and their affinity to be comparable to that of E2. It is interesting to note that deoxybenzoin DB2 showed to be ERβ selective for ( ∼ 15-fold), which is less than the selectivity of genistein and coumestrol, but higher than that of daidzein.…”