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Results for “Estrogen Receptor Modulators”

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PubMed2005

Selective estrogen receptor modulators (SERMs) for the brain: current status and remaining challenges for developing NeuroSERMs.

Multiple issues regarding the efficacy of estrogen action in the brain remain unresolved. These include the timing, formulation and duration of the therapy intervention. Moreover, issues of thrombotic and neoplastic risks must be factored into the design of estrogen alternatives developed to prevent age-associated neurodegenerative disorders, as well as other climacteric symptoms such as hot flush and sleep dysfunction. One strategy to address these issues is to develop molecules that selectively target and activate estrogen mechanisms of action in the brain while avoiding activation of estrogen receptors peripheral to the brain, particularly in reproductive organs. An overview of recent advances in our understanding of the molecular mechanisms of estrogen action is discussed in the context of designing an efficacious NeuroSERM that will activate cellular, biochemical and genomic events required for the promotion of memory function and neuronal survival. Pharmacological analyses of estrogen receptor subtypes and the case for a membrane-associated estrogen receptor splice variant in mediating these mechanisms are provided along with a summary of the activation profiles of existing clinically relevant estrogen alternatives or SERMs in neurons. Results of these endeavors have yielded insights into strategies for developing novel molecules with NeuroSERM potential in order to prevent brain related climacteric symptoms and neurodegenerative diseases.

Brain↗
PubMed2002

Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention.

Tamoxifen has not only proved to be a valuable treatment for estrogen receptor (ER)-positive breast cancer, but is also a pioneering medicine for chemoprevention in high-risk pre- and postmenopausal women. Insights into the pharmacology and toxicology of tamoxifen have led to the recognition of selective ER modulators (SERMs) with estrogen-like actions in maintaining bone density and in lowering circulating cholesterol, but antiestrogenic actions in the breast. Raloxifene, a related SERM, is now available to treat osteoporosis and is also being tested as a preventive for breast cancer and coronary heart disease. Emerging knowledge about the action of SERMs will provide clues for the design of mechanism-based medicines.

Animals↗
PubMed2006

The effects of the selective estrogen receptor modulators, methyl-piperidino-pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus.

Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P <or= 0.0001-0.001). To determine the in vivo uterine effects of these compounds, ovariectomized wild-type (WT) and estrogen receptor-beta knockout (ERbetaKO) mice were treated with 25, 50, 100, or 150 microg of each compound. Although raloxifene caused no significant increase in uterine weight, the presumptive ERalpha antagonist, MPP (25-150 microg) increased uterine weight, and cell proliferation significantly relative to vehicle control in WT and ERbetaKO mice (P <or= 0.001). However, MPP did not increase uterine wet weight as effectively as beta-estradiol (P <or= 0.0001), and administration of either 50 microg of MPP or raloxifene effectively reversed the positive effects of 50 and 100 microg beta-estradiol. Unexpectedly, in view of the in vitro studies, MPP and raloxifene treatment of ovariectomized mice did not induce apoptosis of the luminal epithelial cells but rather these compounds induced apoptosis of the underlying uterine stromal cells. These results demonstrate that MPP and raloxifene can exert apparently contrasting in vitro versus in vivo effects, and that they have mixed agonist/antagonist action on murine uterine ERalpha in vivo.

Animals↗
PubMed2006

Rapid synthesis of 4-benzylidene and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans as potential selective estrogen receptor modulators (SERMs) using McMurry coupling reaction.

7-Methoxy-4-(4-methoxybenzylidene)-2-substituted phenyl-benzopyrans I and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans II carrying different alkylamino residues, designed as estrogen receptor (ER) binding ligands, were successfully synthesized through the McMurry coupling reaction of substituted benzaldehyde/substituted benzophenones and 2-hydroxyphenyl-7-methoxy-chroman-4-one in presence of lithium aluminum hydride and titanium (IV) chloride (LAH-TiCl(4)). Self-coupling of carbonyl reactants led to the formation of several side products. The prototypes were evaluated for their relative binding affinity (RBA), as well as their estrogenic and antiestrogenic activities. High order of estrogenic activity (>50% gain) observed with compounds 3, 7a, 7b, 7c, 8, and 10a and also their partial estrogen antagonistic activity (> or =15%) at the uterine level points toward successful designing of the compounds. Compounds 4, 7a, 7b, 7c, and 10a also possessed significant anticancer activity against human adenocarcinoma cell line (MCF-7 cell line) that may be related to their estrogen-dependent action.

Benzylidene Compounds↗
PubMed2000

[Physiopathology of bone loss and pharmacologic approach of selective estrogen receptor modulators].

Osteoclastic resorption increases at menopause and remains high during aging. The complex mechanism responsible for this increase involves cytokines and growth factors secreted by stromal cells and/or by osteoblasts and cells in the hematopoietic microenvironment. Although estrogen receptors have been found mainly on osteoblasts and their precursors, the stromal cells, they have also been demonstrated on osteoclast precursors. Raloxifene is a selective estrogen receptor modifier (SERM) that has the beneficial effects of estrogens on bone tissue but no estrogen agonist effects on the breast and uterus. Although recent data have established that the mechanism of action of estrogens and SERMs is far more complex than was previously thought, the reason for the tissue selectivity of these molecules remains unknown.

Animals↗
PubMed2005

Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators.

The splicing factor SPF45 (RBM17) is frequently overexpressed in many solid tumors, and stable expression in HeLa cells confers resistance to doxorubicin and vincristine. In this study, we characterized stable transfectants of A2780 ovarian carcinoma cells. In a 3-day cytotoxicity assay, human SPF45 overexpression conferred 3- to 21-fold resistance to carboplatin, vinorelbine, doxorubicin, etoposide, mitoxantrone, and vincristine. In addition, resistance to gemcitabine and pemetrexed was observed at the highest drug concentrations tested. Knockdown of SPF45 in parental A2780 cells using a hammerhead ribozyme sensitized A2780 cells to etoposide by approximately 5-fold relative to a catalytically inactive ribozyme control and untransfected cells, suggesting a role for SPF45 in intrinsic resistance to some drugs. A2780-SPF45 cells accumulated similar levels of doxorubicin as vector-transfected and parental A2780 cells, indicating that drug resistance is not due to differences in drug accumulation. Efforts to identify small molecules that could block SPF45-mediated drug resistance revealed that the selective estrogen receptor (ER) modulators tamoxifen and LY117018 (a raloxifene analogue) partially reversed SPF45-mediated drug resistance to mitoxantrone in A2780-SPF45 cells from 21-fold to 8- and 5-fold, respectively, but did not significantly affect the mitoxantrone sensitivity of vector control cells. Quantitative PCR showed that ERbeta but not ERalpha was expressed in A2780 transfectants. Coimmunoprecipitation experiments suggest that SPF45 and ERbeta physically interact in vivo. Thus, SPF45-mediated drug resistance in A2780 cells may result in part from effects of SPF45 on the transcription or alternate splicing of ERbeta-regulated genes.

Antineoplastic Agents↗
PubMed2003

Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention.

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E(2)). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E(2) deprivation (LTED) causes "adaptive hypersensitivity". The enhanced responses to E(2) do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E(2) on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERalpha is 4- to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E(2) binds to cell membrane-associated ERalpha, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E(2) produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E(2) involved use of cells which selectively expressed ERalpha in the nucleus, cytosol and cell membrane. We created these COS-1 "designer cells" by transfecting ERalpha lacking a nuclear localization signal and containing a membrane localizing signal. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E(2). Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

Adaptation, Physiological↗