EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium

Labrie, Fernand; Labrie, Claude; Bélanger, Alain; Simard, Jacques; Gauthier, Sylvie F.; Luu‐The, Van; Mérand, Yves; Giguère, Vincent; Candas, Bernard; Luo, Shouqi; Martel, Céline; Singh, S. M.; Fournier, Marc R.; Coquet, A.; Richard, Virgile; Charbonneau, Ronald; Charpenet, G.; Tremblay, André; Tremblay, Gilles; Cusan, Lionel; Veilleux, Raymonde

doi:10.1016/s0960-0760(99)00065-5

Cited by 154 publications

(143 citation statements)

References 176 publications

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“…We have previously observed in the rat a very strong (-50%) cholesterol-lowering action of ACOL. [14][15][16] The milder hypocholesterolemic action of ACOL in the present study is not surprising given that mice are generally more resistant to interventions aimed at reducing cholesterolemia. 27,28 ACOL therefore shares the ability to decrease plasma cholesterol, an estrogen-like effect, with other SERMs such as tamoxifene, 29 raloxifene, 30 tibolone 31 and miproxifene phosphate 32 that have been studied in various animal models.…”

Section: Discussionmentioning

confidence: 60%

“…This estrogen-like effect of the SERM confirms previous findings in intact and ovariectomized rats, in which ACOL treatment was shown to reduce markedly weight (mainly fat) accretion. [14][15][16] In both Acolbifene in ERa KO mouse C Lemieux et al female and male ERa KO mice, ACOL was unable to prevent weight and fat gain, and even tended to increase weight gain in female mice. This finding establishes that the lowering action of ACOL on weight gain is mediated via an interaction with the ERa.…”

Section: Discussionmentioning

confidence: 99%

“…Selective estrogen receptor modulators (SERMs), which reduce the risk of estrogen-related cancers but at the same time display estrogen-like actions in other metabolic pathways, constitute a promising avenue for such alternative therapies. 14 We have previously demonstrated beneficial changes in body weight and the lipid profile of female rats following chronic treatment with the fourth-generation SERM Acolbifene (ACOL). 15,16 The drug was shown in rats to decrease greatly body weight gain, mostly fat mass, mainly through a reduction in food intake.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

et al. 2005

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OBJECTIVE:The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs a and b, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERa knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERa KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERa KO mice. ACOL reduced plasma cholesterol in female wild-type mice (À27%), whereas the compound remained ineffective in their ERa KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERa.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

et al. 2005

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“…30 The K D value of OHT (5.7 nM) is also within the range of 0.2−18 nM obtained by other reported methods. 30,36,37 Several PFAAs with different chain lengths and acid groups were then measured. Ideally, one would select short-, medium-, and long-chain carboxylic acids and the corresponding sulfonic acids for structural comparison.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

Gao

Guo

2012

Environ. Sci. Technol.

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Perfluoroalkyl acids (PFAAs) have been reported to interfere with the endocrine system in vivo by mimicking endogenous hormone activities and causing adverse effects. Some exoestrogens bind to estrogen receptor (ER) and subsequently induce an ERmediated response. The transcriptional activity of ER is regulated by its distinct conformational states that are the results of ligand binding. In this work, a biosensor based on surface plasmon resonance (SPR) technique was developed which can discriminate between agonist and antagonist of human ERα (hERα) by monitoring the conformation state of the protein induced by ligand binding. The biosensor utilized the specific interaction between hERα and conformation-selective peptides. Six PFAAs with different chain lengths and acid groups were tested by the biosensor, and perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were found to be ER agonists. Kinetic analyses of direct interaction between PFAAs and hERα by SPR revealed that PFOS and PFOA were both weak binders of ER with K D values of 2.19 and 107 μM respectively, whereas the other four PFAAs did not bind with ER. To understand the differences in ER binding affinity and estrogenic activity among the six PFAAs, molecular docking based on the crystal structure of hERα ligand binding domain was performed. PFOS and PFOA were efficiently docked with hERα and formed hydrogen bonds with Arg394 in a manner similar to estradiol. Overall, the two 8-carbon PFAAs were assessed as weak agonists of hERα and are of potential concern.

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“…Raloxifene (Ral), on the other hand, has less oestrogenic effects on uterus, but the same beneficial effects on bone and lipid metabolism (Delmas et al, 1997;Barrett-Connor et al, 1999;Cohen et al, 2000) while it is an antagonist of oestrogen action in the breast (Gottardis and Jordan, 1987;Cummings et al, 1999). Other SERMs like idoxifene (Idox) (Chander et al, 1991;Nuttall et al, 1998), GW 5638 (Willson et al, 1994(Willson et al, , 1997Connor et al, 2001) and EM 800 (Luo et al, 1998;Labrie et al, 1999;Martel et al, 2000) are different from tamoxifen and based on their activity in the rodent uterus are more closely related to raloxifene. Resveratrol (Res) does not formally belong to the SERM family, because it is a phytoestrogen found in the plants (Jang et al, 1997), however Res has similar in vivo characteristics to the SERMs (Mizutani et al, 2000;Bhat and Pezzuto, 2001;Wu et al, 2001).…”

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confidence: 99%

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Levenson¹,

Kliakhandler²,

Svoboda³

et al. 2002

Br J Cancer

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The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERa or mutant 351 ERa. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10 79 or 10 78 M oestradiol; with 10 76 M 4-hydroxytamoxifen; with 10 76 M raloxifene; with 10 76 M idoxifene, with 10 76 M EM 652, with 10 76 M GW 7604; with 5610 75 M resveratrol and with 10 76 M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERa and clustered together with EM 652 for cells expressing mutant 351 ERa. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

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EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium

Cited by 154 publications

References 176 publications

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

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