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At least 19 recordsLinked to original sources
PubMed2004

BRG1/BRM and prohibitin are required for growth suppression by estrogen antagonists.

Estrogen antagonists are universally employed in the breast cancer therapy, although antagonist therapy is limited by the inevitable development of cellular resistance. The molecular mechanisms by which these agents inhibit cellular proliferation in breast cancer cells are not fully defined. Recent studies have shown the involvement of the E2F pathway in tamoxifen-induced growth arrest. We show that an E2F repressor, prohibitin, and the chromatin modifiers Brg1/Brm are required for estrogen antagonist-mediated growth suppression through the estrogen receptor, and that their recruitment to native promoter-bound E2F is induced via a JNK1 pathway. In addition, we demonstrate major mechanistic differences among the signaling pathways initiated by estrogen, estrogen deprivation, and estrogen antagonists. Collectively, these findings suggest that the prohibitin/Brg1/Brm node is a major cellular target for estrogen antagonists, and thereby also implicate prohibitin/Brg1/Brm as potentially important targets for breast cancer therapy.

Anthracenes↗
PubMed1975

Modulation of uterine morphology and growth by estradiol-17beta and an estrogen antagonist.

The estrogen antagonist C1628 maintains sustained hypertrophy of the uterine epithelium and the synthesis of many proteins including peroxidase. C1628 is a progestogen, inducing secretion of the protein by surface epithelial and glandular cells. C1628 is a connective tissue mitogen, inducing DNA synthesis in fibroblasts and the endothelium. C1628 and estrogen share these properties mentioned above. Estrogen, however, induced moderate growth of the mucosa within a 24-h period and massive hyperplasia of the mucosa within a 24-h period thereafter. C1628 alone, or in combination with estradiol, does not have mitogenic effect on the mucosa, and in fact blocks the mitotic response normally induced by estrogen alone.

Aging↗
PubMed1992

Opposite regulation of cAMP concentration in the quail oviduct and the mouse uterus by tamoxifen. Correlation with estrogen-antagonist and estrogen-agonist activity.

The ability of estradiol and tamoxifen to regulate cAMP levels and cAMP phosphodiesterase activities has been determined in the quail oviduct and in the mouse uterus. In the quail, tamoxifen (1 mg/kg daily for 3 days) had no effect on oviducal growth but significantly increased cAMP concentration (+49%). Injected concurrently with estradiol, tamoxifen completely inhibited oviduct growth as well as the increase of cAMP phosphodiesterase activity induced by the hormone alone and increased cAMP concentration (+229% over estradiol treated group). In the mouse, estradiol and tamoxifen displayed uterotrophic activity and increased cAMP phosphodiesterase activity. In both groups, cAMP concentration was greatly reduced (-76% in estradiol treated group; -86% in tamoxifen treated group). The opposite regulation of cAMP levels in the quail oviduct and the mouse uterus by tamoxifen reflected large differences in the contribution of calmodulin-dependent and -independent forms of phosphodiesterase to the hydrolysis of cAMP in the two models and the fact that tamoxifen stimulated the activity of the calmodulin-independent isoenzyme, while it competitively inhibited the activation of the calmodulin-dependent isoenzyme by calmodulin. Several lines of evidence strongly suggest that the regulation of cAMP levels is involved in growth-inhibiting or growth-promoting activity of tamoxifen.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Effects of estrogen antagonists on estradiol-enhanced radiation transformation in vitro.

We have previously reported that radiation and 17 beta-estradiol can induce transformation in vitro in C3H 10T1/2 cells. In the present series of experiments, we have observed that antagonists of estrogen action, such as c-AMP activating agents (theophylline and dibutyryl c-AMP) and the anti-estrogen, tamoxifen, suppress radiation/17 beta-estradiol enhanced transformation in vitro. None of these known estrogen antagonists had a significant effect on transformation induced by radiation alone. Our results with added dibutyryl c-AMP, theophylline and tamoxifen suggest that estrogen receptor complex formation may play a role in estrogen-enhanced radiation transformation in vitro.

Bucladesine↗
PubMed1992

The binding of estrogen and estrogen antagonists to the estrogen receptor.

The model of the estrogen receptor as a dimer of identical, interacting subunits and data obtained by Sasson and Notides (1988, Mol. Endocrinol. 2, 307-312) were used to find the standard free energy changes that describe the binding of estradiol and 4-hydroxytamoxifen to the estrogen receptor. For the binding of estradiol or 4-hydroxytamoxifen to the estrogen receptor the data do not deviate systematically from the best fit to the model. The standard free energy change for binding of one molecule of estradiol at one site and one molecule of 4-hydroxytamoxifen at the second site of estrogen receptor indicates that 4-hydroxytamoxifen antagonizes the binding of estradiol to the estrogen receptor.

Binding, Competitive↗
PubMed1999

Inhibition of dendritic spine induction on hippocampal CA1 pyramidal neurons by a nonsteroidal estrogen antagonist in female rats.

Estrogens regulate the formation of excitatory synaptic connections in the hippocampus of female rats. Because the adult hippocampus has a very low concentration of intracellular estrogen receptors, it is unclear whether a conventional genomic mechanism is involved. Nonsteroidal estrogen antagonists are useful tools to study estrogen action because they can provide pharmacological data in favor of a particular pathway of estrogen action and evidence against other pathways. To investigate the role of intracellular estrogen receptors in the estrogen induction of synapse formation, we took advantage of previous studies in which we had shown that an estrogen antagonist, CI-628, enters the brain and blocks estrogen induction of progestin receptors to study whether the same antagonist would either mimic or block effects of estradiol to induce excitatory spine synapses. Using silver impregnation of neurons by the single section Golgi technique and morphometric analysis, we found that CI-628 effectively prevented estrogen induction of spines on CA1 pyramidal neurons, without having any agonist effects of its own. This result is consistent with an action of estradiol via intracellular estrogen receptors that are known to be expressed by interneurons within the hippocampus.

Animals↗
PubMed2001

Interaction with anti-implantation and estrogen antagonistic activities of dl-ormeloxifene, a selective estrogen receptor modulator, by tetracycline in female Sprague-Dawley rats.

Among the 10 commonly used therapeutic agents investigated, concurrent oral administration of tetracycline (140 mg/kg) twice daily on Days 1-5 post-coitum (pc) interfered with the post-coital anti-implantation activity and almost completely abolished estrogen antagonistic activity of the single anti-implantation (1.5 mg/kg, orally) dose of dl-ormeloxifene administered on Day 1 pc, resulting in the occurrence of resorbed implantations in 50% of the females. However, no such interaction was evident when tetracycline was administered intramuscularly or when ormeloxifene was administered at twice its anti-implantation dose. There was no effect of ormeloxifene and/or tetracycline treatment on serum estradiol and progesterone levels, and all animals presented apparently normal corpora lutea. Ormeloxifene administered per se inhibited aminopyrine-N-demethylase (AD), glucose-6-phosphate dehydrogenase (G-6-PDH) and glutathione-S-transferase (GST) in the liver on the day of maximal endometrial receptivity, which was prevented by tetracycline co-administration. Aniline hydroxylase and AD were not detected in small intestine or uterus in vehicle control or any of the treatment groups. There was, however, no effect of ormeloxifene plus tetracycline treatment on serum total alkaline phosphatase activity. Findings suggest that interference with anti-implantation action of ormeloxifene by tetracycline might be due primarily to the almost complete abolition of its estrogen antagonistic activity at the uterine level, effected by decreased bioavailability of ormeloxifene and/or its active metabolite(s) by altered enterohepatic recirculation because of the effect on gut microflora. This might alternatively be related to an increased rate of its metabolism and elimination from the system via prevention of ormeloxifene-induced inhibition of hepatic AD, G-6-PDH, and GST, which, by effecting a decreased rate of metabolism, might be responsible for prolonged (approximately 120 h) duration of estrogen antagonistic/anti-implantation action of ormeloxifene in this species.

Animals↗
PubMed2003

Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists.

Breast cancer resistance protein (BCRP), an ATP-binding cassette transporter, confers resistance to a series of anticancer agents such as SN-38, mitoxantrone, and topotecan. In a previous study, we found that estrogens reverse drug resistance of BCRP-expressing cells. In this study, estrogen antagonists, estrogen agonists, and their derivatives were evaluated for BCRP-reversing activity. First, compounds were tested for effects on the cellular accumulation of topotecan in BCRP-transduced K562 cells (K562/BCRP). Next, these compounds were examined for their ability to reverse SN-38 and mitoxantrone resistance in K562/BCRP cells. Among commercially available estrogen antagonists and agonists tested, diethylstilbestrol showed the strongest BCRP-reversing activity. Diethylstilbestrol increased the cellular accumulation of topotecan and reversed drug resistance in K562/BCRP cells but showed marginal or no effect in parental K562 cells. The reversal activities of estrone and diethylstilbestrol were more prominent for mitoxantrone than for SN-38. Tamoxifen and toremifene were also found to enhance topotecan uptake in K562/BCRP cells. Next, various tamoxifen derivatives were screened for anti-BCRP activity. In the first cycle of screening with 14 compounds, TAG-11 showed the strongest effect. In the second cycle of screening of 25 TAG-11-related compounds, TAG-139 showed the strongest effect. Reversal of SN-38 and mitoxantrone resistance in K562/BCRP cells by TAG-139 was 5-fold stronger than that by estrone. Dose-dependent characteristics of drug resistance reversal with estrone and TAG-139 were very similar, suggesting that estrone and tamoxifen derivatives interact with the same drug-binding site of BCRP. Derivatives of antiestrogens that exhibit no other biological effects promise to be useful in overcoming BCRP-mediated drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity.

In an effort to prepare nonsteroidal antiestrogens demonstrating greater antagonism and less intrinsic estrogenicity than those currently available, a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives was synthesized. These compounds were prepared by Friedel-Crafts aroylation of appropriate O-protected 2-arylbenzo[b]thiophene nuclei with basic side-chain-bearing benzoyl chlorides followed by removal of the protective groups to provide the desired compounds containing both hydroxyl and basic side-chain functionality. A particularly useful method for the cleavage of aryl methoxy ethers without removal of (dialkylamino)ethoxy side chain functionality elsewhere in the molecule was found to be AlCl3/EtSH. The benzothiophene derivatives were tested for their ability to inhibit the growth-stimulating action of estradiol on the immature rat uterus. Seemingly minor changes in the side-chain amine moiety were found to have profound effects on the ability of the compounds to antagonize estradiol. Analogues having basic side chains containing cyclic (pyrrolidine, piperidine, and hexamethyleneamine) moieties were found to have less intrinsic estrogenicity and to antagonize estradiol action more completely than their noncyclic counterparts. The most effective antiestrogen in the series, compound 44, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, elicited a modest uterotropic activity that did not increase with increasing dose. In antagonism of estradiol, 44 exhibited a degree of inhibition surpassing that of tamoxifen at any dose tested. The new benzothiophene antiestrogen was also shown to have high affinity for rat uterine cycloplasmic estrogen receptor and to be an inhibitor of the growth of DMBA-induced rat mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

New estrogenic antagonists bearing dicarba-closo-dodecaborane as a hydrophobic pharmacophore.

We have designed and synthesized estrogen antagonists bearing dicarba-closo-dodecaborane (carborane) as a hydrophobic pharmacophore based on the structure of 1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane, a potent estrogen agonist that we reported previously. Compounds with a long alkyl chain bearing an amide moiety on the carborane skeleton (6, 7) showed estrogen antagonistic activity in a luciferase reporter gene assay using COS-1 cells transfected with a rat ER alpha-expression plasmid and as an appropriate reporter plasmid.

Animals↗
PubMed1989

Points of action of estrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle.

Tamoxifen and other structurally related nonsteroidal antiestrogens possess properties in addition to their estrogen antagonist activity including inhibition of both calmodulin and protein kinase C. The present studies were designed to test whether the estrogen-reversible (estrogen receptor mediated) and estrogen-irreversible effects of nonsteroidal antiestrogens on cell cycle progression in vitro were mediated at the same or different points within the cell cycle and if the estrogen-irreversible effects coincided temporally with that of a calmodulin antagonist, R24571. Initial experiments investigated the effects of ICI 164384, a pure estrogen antagonist, on proliferation kinetics in asynchronous cultures of MCF-7 human breast cancer cells. At concentrations greater than 1 nM ICI 164384 significantly reduced growth rate while at greater than or equal to 50 nM, ICI 164384 completely arrested growth after the first 24 h of exposure. Concentrations up to 5 microM failed either to cause more profound effects on growth or induce cytotoxicity. Growth inhibition was associated with a decrease in the proportion of S phase cells and an accumulation of cells in G1 phase, and was completely reversed by the simultaneous addition of equimolar estradiol. In order to identify the points of action within the cell cycle of ICI 164384, and the estrogen-reversible and estrogen-irreversible components of the nonsteroidal estrogen antagonist, hydroxyclomiphene, and the calmodulin antagonist, R24571, experiments were undertaken with MCF-7 cells synchronized by mitotic selection. The mean point of action was assessed by delaying addition of the drugs for increasing time periods following mitotic selection and using DNA flow cytometry to determine the proportion of the population affected by drug administration at a specific time within G1 phase. These studies showed that sensitivity to ICI 164384 was restricted to the early part of G1 phase and that the mean time of action was 4.9 h after the beginning of G1 for this pure estrogen antagonist. The mean times of action of the estrogen-reversible (4.1 h into G1 phase) and estrogen-irreversible (4.1 h) mechanisms of action of hydroxyclomiphene, and R24571 (4.0 h), all appeared to be within a similar time frame in early to mid G1 phase. It is concluded that ICI 164384 inhibits breast cancer cell proliferation by inducing a transition delay in G1 phase and that the point of action of this pure estrogen antagonist in early G1 phase is indistinguishable temporally from that of nonsteroidal antiestrogens and calmodulin antagonists.

Breast Neoplasms↗
PubMed2000

A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence.

Estrogen antagonists inhibit cell cycle progression in estrogen-responsive cells, but the molecular mechanisms are not fully defined. Antiestrogen-mediated G(0)/G(1) arrest is associated with decreased cyclin D1 gene expression, inactivation of cyclin D1-cyclin dependent kinase (Cdk) 4 complexes, and decreased phosphorylation of the retinoblastoma protein (pRb). We now show that treatment of MCF-7 breast cancer cells with the pure estrogen antagonist ICI 182780 results in inhibition of cyclin E-Cdk2 activity prior to a decrease in the G(1) to S phase transition. This decrease was dependent on p21(WAF1/Cip1) since treatment with antisense oligonucleotides to p21 attenuated the effect. Recruitment of p21 to cyclin E-Cdk2 complexes was in turn dependent on decreased cyclin D1 expression since it was apparent following treatment with antisense cyclin D1 oligonucleotides. To define where within the G(0) to S phase continuum antiestrogen-treated cells arrested, we assessed the relative abundance and phosphorylation state of pocket protein-E2F complexes. While both pRb and p107 levels were significantly decreased, p130 was increased 4-fold and was accompanied by the formation of p130.E2F4 complexes and the accumulation of hyperphophorylated E2F4, putative markers of cellular quiescence. Thus, ICI 182780 inhibits both cyclin D1-Cdk4 and cyclin E-Cdk2 activity, resulting in the arrest of MCF-7 cells in a state with characteristics of quiescence (G(0)), as opposed to G(1) arrest.

Breast Neoplasms↗
PubMed1999

Carboxylic acid analogues of tamoxifen: (Z)-2-[p-(1, 2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells.

The triarylethylene estrogen mimetic (E, Z)-4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4) represents a novel class of estrogen receptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist and antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in triarylethylenes to improve ER affinity and estrogen antagonist properties, were prepared with the ultimate aim of identifying substances with improved estrogenicity exclusive of reproductive tissues. Thus, the side chain of 4 was elongated to give oxybutyric acid 13, which was further altered by (a) repositioning of its p-hydroxyl to the neighboring m-position (12) and (b) ethylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affording 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for human ERalpha as 4, and its antiproliferative effect in MCF-7 cells was greater than that of 1. Dihydro analogue 14, which was conformationally similar to cis-13, had very low ER affinity and antiestrogenicity, and m-hydroxy analogue 12 also had reduced ER affinity and potency, but its MCF-7 cell antiproliferative efficacy was retained. Modest ER affinity and antiproliferative potency were seen with 8, in which phenolic and phenyl rings were trans to one another, but 9, in which these rings were cis, was inactive. Our findings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antagonist effects in MCF-7 cells.

Antineoplastic Agents↗
PubMed1994

The beneficial effect of the estrogen antagonist, tamoxifen, on experimental systemic lupus erythematosus.

OBJECTIVE: To determine the effects of the estrogen antagonist, tamoxifen, on the development and the course of experimental murine systemic lupus erythematosus (SLE). METHODS: SLE was induced in naive BALB/c female mice by injection of the human monoclonal anti-DNA antibody bearing the 16/6 idiotype (Id). Six weeks following immunization, when high levels of autoantibodies were demonstrated, the mice were treated with tamoxifen (200-800 micrograms/mouse twice a week) up to a period of 8 months. In several mouse groups tamoxifen treatment was started as late as one year following the immunization with the 16/6 Id when overt disease was already observed. RESULTS: Tamoxifen treatment had no effect on the 16/6 Id induced autoantibody production. However, the 16/6 Id immunized and tamoxifen treated mice demonstrated normal numbers of white blood cells (WBC) and thrombocytes while the untreated groups had significant leukopenia and thrombocytopenia. Similarly, persistent proteinuria and immune complex deposits in the kidneys were observed in the 16/6 Id immunized mice whereas no such deposits were found in kidney sections of 16/6 Id immunized mice that were treated with tamoxifen. Delayed tamoxifen treatment (starting a year following the immunization) also demonstrated beneficial therapeutic effects. CONCLUSION: These studies demonstrate therapeutic effects of tamoxifen on murine experimental SLE suggesting a possible role for this estrogen antagonist in the treatment of human SLE and related disorders.

Animals↗
PubMed1990

In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium.

The human endometrial model for in vitro evaluation of estrogenic, estrogen antagonistic, and progestagenic effects of endogenous steroids, natural products or synthetic drugs was applied to the study of Org OD-14, an analog of norethynodrel developed by Organon International, Oss, The Netherlands, and some of its metabolites. Estrogen antagonistic actions of Org OD-14 and its 4-ene isomer were evident from their ability to suppress the enhancement of PGF2 alpha output elicited by estradiol on fragments of secretory endometrium and to decrease the rate of output of the prostaglandin by proliferative tissue, already stimulated by endogenous estrogens. These inhibitory effects were similar to those obtained with progesterone and do not appear to involve competition for the estrogen receptor since the antiestrogen 4-hydroxyamoxifen was not active in parallel incubations of proliferative endometrium. The progestagenic effects of Org OD-14 and its 4-ene isomer were also evident from their capability to enhance estradiol 17 beta-dehydrogenase activity and glycogen accumulation in specimens of proliferative endometrium. Estrogenic effects of the 3 alpha- and 3 beta-hydroxy metabolites of Org OD-14 were demonstrated by their stimulatory actions on PGF2 alpha output during incubations of secretory endometrium. The estrogenic and progestagenic actions of these compounds are in general agreement with their relative affinity for binding to the estradiol and progesterone receptors, although their actions may be influenced by intracellular metabolism in the endometrial tissue. For instance, the similarity in progestagenic activity of Org OD-14 and the 4-ene isomer, contrasting with their different affinities for the progesterone receptor, may result from in situ isomerization of Org OD-14 to the 4-ene metabolite.

Cells, Cultured↗
PubMed1993

The estrogen antagonist ICI 182,780 reduces cancellous bone volume in female rats.

Although estrogen is thought to protect the skeleton by inhibiting bone resorption, we have also found that in the rat, estrogen stimulates cancellous bone formation. However, the extent to which the various skeletal actions of estrogen are mediated by classical estrogen receptors remains unclear. Although estrogen receptor antagonists such as tamoxifen have been used to study this question, interpretation of the results is complicated by the fact that this agent also acts as a partial estrogen agonist. However, the recent development of estrogen antagonists devoid of agonist activity provides an opportunity to explore this question further. We, therefore, investigated the effect of administration of the pure estrogen antagonist ICI 182,780 on the skeleton of adult female rats. We found that ICI 182,780 reduced bone volume at the proximal tibial metaphysis by approximately 30%, associated with an increase in osteoclast surface. We then investigated the effect of ICI 182,780 on the anabolic action of estrogen. We used ovariectomized rats treated with 3-amino-1-hydroxypropylidene-1-bisphosphonate to inhibit bone resorption, thereby preventing any increase in bone formation as a result of the stimulation of bone resorption due to estrogen deficiency. 17 beta-Estradiol (1 micrograms/kg) stimulated cancellous bone formation in such animals by approximately 8-fold; this increase was abolished when ICI 182,780 was also given. In contrast, ICI 182,780 affected neither longitudinal nor periosteal tibial growth in either intact animals or ovariectomized rats given estradiol or vehicle. We conclude that ICI 182,780 reduces cancellous bone volume in the rat by antagonizing estrogen's actions on bone formation and resorption, suggesting that these processes are both mediated by classical estrogen receptors.

Animals↗
PubMed2002

[Effect of mitogen-activated protein kinase signal transduction in non-estrogen antagonistic mechanism of tamoxifen].

OBJECTIVE: To investigate the effect of mitogen-activated protein kinase (MAPK) signal cascade in the non-estrogen antagonistic mechanism of tamoxifen (TAM). METHODS: Human breast cancer cells MCF-7 were cultured. TAM, PD98075, inhibitor of MAPK kinase (MEK), or TAM + PD98075 was added into the culture media, followed by methyl thiazolyl tetrazolium (MTT) and DMSO. Then the 542nm absorption value was measured and the growth curve was drawn. Western blot was used to measure the expression of p-extracellular signal-regulated kinase (ERK) in MCF-7 cells. Flow cytometry was applied to analyze the cell cycle and apoptosis. RESULTS: The optical density representing the relative expression of p-ERK was lower successively in the control, TAM, PD09875, and TAM + PD09875 groups. The apoptotic rate of MCF-7 cells was 6.44%, 8.3%, 36.5% and 53.5% in the control, PD98075, TAM, and TAM + PG98075 groups respectively The rate of cells in G(0)G(1) phase was 74.25%, 79.76%, 84.02%, and 95.82% in those groups respectively. Ther rate o cells in S phase was 21.03%, 15.22%, 11.43%, and 2.22% respectively in those groups. The rate of cells in G(2)M phase was 4.71%, 5.02%, 4.52%, and 1.96% respectively in those groups. CONCLUSION: MAPK signal transduction pathway plays a certain role in the non-estrogen antagonistic mechanism of tamoxifen.

Antineoplastic Agents, Hormonal↗