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PubMed2005

4-Hydroxytamoxifen inhibits proliferation of multiple myeloma cells in vitro through down-regulation of c-Myc, up-regulation of p27Kip1, and modulation of Bcl-2 family members.

PURPOSE: Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies. Our approach was to analyze the in vitro effects of a selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT), on six multiple myeloma cell lines. EXPERIMENTAL DESIGN: Cultured multiple myeloma cells were treated with various 4-OHT concentrations and the cellular response was studied: cell proliferation, cell viability, induction of apoptosis, caspase activities, and expression of signaling proteins. RESULTS: We found that pharmacologic concentrations of 4-OHT inhibit cell proliferation (4 of 6 cell lines). This inhibition is achieved by two independent events: a block at the G(1) phase of the cell cycle and the induction of apoptotic death. The cellular response to 4-OHT depends on the presence of functional estrogen receptors. 4-OHT treatment activates an intrinsic mitochondrial caspase-9-dependent pathway but not the Fas/FasL death pathway. Signaling pathways known to be involved in the survival and/or proliferation of multiple myeloma cells are not affected by 4-OHT treatment. 4-OHT-induced G(1) arrest is accompanied by the up-regulation of the cell cycle inhibitor p27(Kip1) and the down-regulation of c-Myc. Among the Bcl-2 family members tested, the proapoptotic BimS protein is induced whereas the antiapoptotic protein Mcl-1 is decreased. CONCLUSIONS: Although the effects of 4-OHT are observed at micromolar concentrations, cellular mechanisms responsible for G(1) arrest, as well as apoptosis induction, are similar to those observed in breast cancer cells. Our data support the concept that 4-OHT may represent an alternative approach to inhibit proliferation and induce apoptosis of multiple myeloma cells.

Apoptosis↗
PubMed2002

Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma.

Uterine leiomyomas are the most common gynecologic neoplasm in reproductive-age women. While it is clear that hormonal factors play a prominent role in this disease, how steroid hormones contribute to disease etiology or may be utilized as targets for intervention are currently areas of active scientific investigation. To study the impact of hormones on uterine leiomyomas, the Eker rat has been developed as an in vivolin vitro animal model system for these tumors. Spontaneous leiomyomas arise in intact Eker rats with a high frequency and leiomyoma-derived cell lines from these animals maintain the biochemical and physiological characteristics of the tumors from which they were obtained. Using this animal model system, it has been established that tumor development is absolutely dependent on steroid hormones and that sensitivity/responsiveness to estrogen is enhanced in tumors and tumor-derived cell lines. Modulation of hormonal milieu, such as that which naturally occurs during pregnancy, can effectively inhibit tumor development. The hormone responsiveness of these tumors makes them good candidates for hormonal therapy. Selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene hold promise as potential therapeutic agents for this disease. SERMs inhibit proliferation of leiomyoma-derived cell lines in vitro, repress the growth of these lines in nude mice, and, when administered over a 2- to 4-month course of treatment to Eker rats, reduce tumor incidence by more than 50%. In addition to endogenous hormones, xenoestrogens in our environment (e.g., phytoestrogens, organochlorine pesticides, pharmacologic compounds) are of potential concern with regards to their impact on this disease. These environmental estrogens have been shown to promote the growth of leiomyoma cells in vitro and in vivo. Further elucidation of the role of these and other hormonal and reproductive factors in the development of uterine leiomyoma will be invaluable for increasing our understanding of the etiology of this disease and developing new therapeutic strategies to help to reduce the negative impact of uterine leiomyomas on women's health.

Animals↗
PubMed2003

Emerging role of aromatase inhibitors in the adjuvant setting.

Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.

Antineoplastic Agents↗
PubMed1999

Biologic agents and innovative interventional approaches in the management of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a difficult disease to study, having a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for SLE. These products are designed to specifically interfere with the following immunologic processes: T cell activation/T cell-B cell collaboration, production of anti-double-stranded DNA antibodies, deposition of anti-double-stranded DNA antibody complexes, complement activation, and immune complex deposition and cytokine activation and modulation. More aggressive interventions include gene therapy and stem cell transplantation. Immunomodulatory agents recently examined in patients with SLE include: thalidomide, AS101, 2' chlordeoxyadenosine, mycophenolate mofetil, and bindarit. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, selective estrogen receptor modulators, and the prolactin inhibitor, bromocriptine. A variety of these biologic and pharmaceutical agents offer promise as potential therapies. Active participation in clinical trial efforts to develop international consensus regarding trial methodology and outcome measures are crucial to the development of these innovative therapies.

Animals↗
PubMed2003

Effects of raloxifene on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis.

BACKGROUND: Premature amenorrhea and hypoestrogenism and lack of hormone replacement therapy after menopause have been frequently reported in uremic women on dialysis. Therefore, in addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. In addition, these patients are at higher risk for hyperlipidemia, arteriosclerosis, and subsequent coronary heart disease and stroke. Recent evidence has suggested that hormone replacement therapy (HRT) in postmenopausal women could have several beneficial effects as well as potentially serious risks. Great efforts have been made to identify therapeutic alternatives that would have the benefits of estrogen on brain and bone without its adverse effects on breast and endometrium. In the present study, we evaluated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on bone metabolism and serum lipids in postmenopausal women on chronic hemodialysis. METHODS: We performed a prospective, blind, placebo-controlled, and randomized study. Fifty postmenopausal women on chronic hemodialysis with proven severe osteopenia or osteoporosis by bone densitometry were selected. After a written informed consent, patients were randomized into two groups: 25 women on placebo and 25 women on the study drug, raloxifene hydrochloride, at a dose of 60 mg/day. In all patients, we performed a baseline bone mineral density (BMD) analysis and simultaneously evaluated different biochemical parameters, serum lipids (total low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol and triglycerides) and serum markers of bone resorption (pyridinoline crosslinks). BMD was reassessed after 1 year of therapy. Bone resorption markers were determined every 3 months for 1 year. RESULTS: After 1 year on raloxifene therapy, lumbar spine BMD (trabecular bone) significantly improved, whereas femoral neck BMD (cortical bone) did not change significantly. No changes in BMD were observed at trabecular or cortical sites in the placebo group. Serum pyridinoline levels showed a significant decrease after 6 months on raloxifene that persisted thereafter. Low-density lipoprotein (LDL)-cholesterol decreased significantly in the raloxifene group with no changes in serum triglycerides, total cholesterol, or HDL cholesterol. No significant side effects were observed in the raloxifene group. CONCLUSION: The study demonstrates that after one year on raloxifene, postmenopausal women on hemodialysis have a significant increase in trabecular BMD, decrease in bone resorption markers and LDL-cholesterol values, suggesting that SERMs could constitute a therapeutic alternative to improve bone metabolism and control of hyperlipidemia in these patients. The possible long-term effects of raloxifene remain to be determined.

Aged↗
PubMed2005

Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators.

Estrogen receptor (ER), mediating estrogen-signaling stimuli, is a dominant regulator and a key therapeutic target in breast cancer etiology and progression. Endocrine therapy, blocking the ER pathway, is one of the most important systemic therapies in breast cancer management, but de novo and acquired resistance is still a major clinical problem. New research highlights the role of both genomic and nongenomic ER activities and their intimate molecular crosstalk with growth factor receptor and other signaling kinase pathways in endocrine resistance. These signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. Thus, these signal transduction receptors and signaling molecules may serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance. Compelling experimental and clinical evidence suggest that the epidermal growth factor/HER2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen. Results from preclinical studies of treatment combinations with various endocrine therapy drugs together with several potent anti-EGFR/HER2 inhibitors are very promising, and clinical trials to see whether this new strategy is effective in patients are now ongoing.

Breast Neoplasms↗
PubMed2006

Raloxifene increases proliferation and up-regulates telomerase activity in human umbilical vein endothelial cells.

Vascular endothelial senescence is involved in human atherosclerosis. Telomerase activity is known to be critical in cellular senescence and its level is modulated by regulation of telomerase catalytic subunit (telomerase reverse transcriptase (TERT)) at both the transcriptional and post-transcriptional levels. Since the cardioprotective effect of estrogen itself has not been ruled out, we examined that of raloxifene, which has been classified as a selective estrogen receptor modulator, on the proliferation and telomerase activity of human umbilical vein endothelial cells (HUVECs). Raloxifene, like estrogen, clearly induced the telomerase activity and human TERT (hTERT) expression via estrogen receptor (ER) alpha and ERbeta. Treatment with raloxifene for 5 days significantly induced cell growth, and either cotreatment with a telomerase inhibitor, 3'-azido-3'-deoxythymidine, or transfection with hTERT-specific small interfering RNA significantly attenuated the raloxifene-induced cell growth. Raloxifene also induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, significantly attenuated the raloxifene-induced telomerase activity. In addition, raloxifene induced both the phosphorylation of hTERT and IkappaB. Moreover, cotreatment with an IkappaBalpha phosphorylation inhibitor, BAY-11-7082, or a specific NFkappaB nuclear translocation inhibitor, SN50, significantly attenuated the raloxifene-induced telomerase activity and the association of NFkappaB with hTERT. These results show that raloxifene induced the up-regulation of telomerase activity not only by the transcriptional regulation of hTERT but also by post-translational regulation of the phosphorylation of Akt and hTERT and the association of hTERT with NFkappaB in HUVECs. Thus, the up-regulation of telomerase activity in vascular endothelial cells might be one mechanism contributing to the potential atheroprotective effect of raloxifene.

Cell Proliferation↗
PubMed1997

Approaches to the management of systemic lupus erythematosus.

Systemic lupus erythematosus is a difficult disease to study with a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for systemic lupus erythematosus, either in murine disease models or in clinical trials. These products are designed to specifically interfere with the following immunologic processes: T-cell activation and T-cell-B-cell collaboration, production of anti-dsDNA antibodies, deposition of anti-dsDNA antibody complexes, complement activation, and deposition, and cytokine activation and modulation. More aggressive interventions include gene therapy and stem-cell transplantation. Recently developed immunomodulators have been studied in patients with systemic lupus erythematosus 2'-Chlorodeoxyadenosine, mycophenolate mofetil, and leflunomide. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, estrogen antagonists, including tamoxifen and selective estrogen receptor modulators, and the prolactin inhibitor bromocriptine. Other promising pharmaceutical interventions include products designed to inhibit synthesis of the proinflammatory mediators: prostaglandins, leukotrienes, and nitric oxide. Although previously regarded as an indication to be avoided in the development of new therapeutics, enthusiasm for studying systemic lupus erythematosus in clinical trials now exists. A variety of biologic and pharmaceutical agents offer promise as potential therapies. As with rheumatoid arthritis, development of these products will benefit from active involvement of rheumatologists and efforts to develop international consensus regarding trial methodology and outcome measures.

Animals↗
PubMed2000

[The modulators of the estrogenic activity].

The biological, pharmacological and therapeutic properties of estrogens/antiestrogens are related to their chemical structure. Tamoxifen, used for the treatment of hormone-dependent breast cancer, and other analogue derivatives of triarylethylene or presenting a cyclic or heterocyclic structure, mimic some of the activities of estrogens. They have major therapeutic potential as selective estrogen receptor modulators in the prevention of breast cancer and various post-menopausal conditions.

Breast Neoplasms↗
PubMed2004

Molecular characterization of the microsomal tamoxifen binding site.

Tamoxifen is a selective estrogen receptor modulator widely used for the prophylactic treatment of breast cancer. In addition to the estrogen receptor (ER), tamoxifen binds with high affinity to the microsomal antiestrogen binding site (AEBS), which is involved in ER-independent effects of tamoxifen. In the present study, we investigate the modulation of the biosynthesis of cholesterol in tumor cell lines by AEBS ligands. As a consequence of the treatment with the antitumoral drugs tamoxifen or PBPE, a selective AEBS ligand, we show that tumor cells produced a significant concentration- and time-dependent accumulation of cholesterol precursors. Sterols have been purified by HPLC and gas chromatography, and their chemical structures determined by mass spectrometric analysis. The major metabolites identified were 5alpha-cholest-8-en-3beta-ol for tamoxifen treatment and 5alpha-cholest-8-en-3beta-ol and cholesta-5,7-dien-3beta-ol, for PBPE treatment, suggesting that these AEBS ligands affect at least two enzymatic steps: the 3beta-hydroxysterol-Delta8-Delta7-isomerase and the 3beta-hydroxysterol-Delta7-reductase. Steroidal antiestrogens such as ICI 182,780 and RU 58,668 did not affect these enzymatic steps, because they do not bind to the AEBS. Transient co-expression of human 3beta-hydroxysterol-Delta8-Delta7-isomerase and 3beta-hydroxysterol-Delta7-reductase and immunoprecipitation experiments showed that both enzymes were required to reconstitute the AEBS in mammalian cells. Altogether, these data provide strong evidence that the AEBS is a hetero-oligomeric complex including 3beta-hydroxysterol-Delta8-Delta7-isomerase and the 3beta-hydroxysterol-Delta7-reductase as subunits that are necessary and sufficient for tamoxifen binding in mammary cells. Furthermore, because selective AEBS ligands are antitumoral compounds, these data suggest a link between cholesterol metabolism at a post-lanosterol step and tumor growth control. These data afford both the identification of the AEBS and give new insight into a novel molecular mechanism of action for drugs of clinical value.

Animals↗
PubMed2004

Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone.

UNLABELLED: Contradictory results whether the endocrine disrupters (ED) benzophenone-2 (BP2), bisphenol A (BPA) and dibutylphtalate (DBP) exert estrogenic effects have been published. Selective estrogen receptor modulators (SERMs) exert estrogenic effects in some but not in all organs and ED may be SERMs. Therefore, we studied their binding properties to recombinant ERalpha and ERbeta protein and their effects in the uterus, vagina and bone of ovariectomized rats. BP2 bound to both receptor subtypes, while BPA had a relatively high ERbeta selectivity. DBP did not bind to ERalpha but with a low affinity to ERbeta. In the uterus, only E2 and BP2 increased uterine weight and the complement C3 but decreased ERbeta gene expression. Discrete effects of BPA and DBP in the uterus were found upon histological examination. In the vagina, BP2 but not BPA and DBP had clear estrogenic effects. E2 and BP2 had antiosteoporotic effects in the metaphysis of the tibia. The serum surrogate parameters of bone metabolism, i.e. osteocalcin and the cross (rat) laps were significantly reduced by E2, an effect shared with BP2 but not by the two other EDs. THE CONCLUSION: BP2 acts as ERalpha and ERbeta agonist mimicking effects of E2, while the effects of BPA and DBP are not pure estrogenic.

Animals↗
PubMed2004

Estrogen receptor-dependent activation of AP-1 via non-genomic signalling.

BACKGROUND: Ligand-bound estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) modulate AP-1-dependent transcription via protein-protein interactions on DNA, in a manner that depends on the type of cells and the subtype of ER. We present here evidence for an additional mechanism by which ERs modulate the transcriptional activity of AP-1. RESULTS: We show that ERs located in the cytoplasm efficiently activate transcription at AP-1 sites in response to 17beta-estradiol, while ERs present in the nucleus repress transcription under the same conditions. 17beta-estradiol-induced activation of the coll-73-luc reporter correlated with cytoplasmic localization of various ERalpha and ERbeta mutant receptors, and was inhibited in the presence of the full estrogen antagonist ICI 182,780 and the MAP-kinase inhibitor UO126. We also show that the selective estrogen receptor modulator (SERM) tamoxifen is as potent as 17beta-estradiol in inducing activation of AP-1 when ERalpha is present in the cytoplasm. CONCLUSIONS: These results suggest that non-genomic signalling is involved in the mechanism by which ERalpha and ERbeta influence AP-1-dependent transcription. We have previously shown that Stat3 and Stat5 are targeted by non-genomic actions of ERs, and the results presented here allow us to conclude that ERs bound to 17beta-estradiol mediate the transcriptional activation of promoters regulated by AP-1 and by Stat proteins via different combinations of signal transduction pathways. Our observations thereby provide new insights into the mechanisms by which ERs act at alternate response elements, and suggest a mechanism by which tamoxifen exerts its action as a tissue-selective agonist.

Journal Article↗
PubMed2004

Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats.

Obesity, from declining estrogen levels after menopause, increases the risk of heart disease, diabetes, and hypertension. Ovariectomy (OVX) in rats is a good model of estrogen insufficiency. The ensuing mild obesity is useful to study how hypoestrogenism alters adiposity. This study examines the hypothesis that in ovariectomized (OVX) rats modification of estrogen levels or treatment with a selective estrogen receptor modulator, raloxifene (RAL), alters leptinemia and modulates leptin receptor (Ob-R) abundance in hypothalamus and white adipose tissue, similar to the modification of adipose status induced by hypoestrogenism. Mid- and long-term studies (7 and 22 wk) were conducted to monitor the change in leptinemia in rats after estrogen loss by OVX and after estrogen replacement by 17beta-estradiol (OVX+E(2)) or RAL treatment (OVX+RAL). Leptin was significantly higher in OVX rats vs. controls, in a time-dependent manner. This effect was reversed by both E(2) and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E(2) or RAL treatment reversed the OVX-induced increases in food intake, body weight, and fat mass content; the modifications of serum parameters were examined to evaluate the different lipid profiles. We also evaluated Ob-R expression in hypothalamus and adipose tissue by Western blot analysis. The expression of the long functional isoform (Ob-Rb) increased at 7 wk only in adipose tissue and decreased at 22 wk in OVX rats in both tissues; these effects were reversed by E(2) or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels.

Adaptation, Physiological↗
PubMed2005

ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks.

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.

Animals↗
PubMed2002

Ultrasonographic assessment of endometrial thickness: a review.

Measurement of endometrial thickness with ultrasonography is a modality commonly used today. Its clinical importance and applications extend throughout the phases of the reproductive lives of women. In premenopausal women, endometrial thickness is used to monitor infertility treatment, while in postmenopausal women with abnormal uterine bleeding it is useful as an initial investigation for endometrial hyperplasia or cancer. Moreover, endometrial thickness can vary with the menstrual cycle and with the use of hormone replacement therapy or selective estrogen receptor modulators. In this review, the use of ultrasound to measure both the premenopausal and postmenopausal endometrium is discussed.

Biopsy↗
PubMed2001

Neuroendocrine effects of raloxifene hydrochloride in postmenopausal women.

Raloxifene is a selective estrogen modulator able to exert an estrogen-like action on some target tissues and a specific antiestrogenic action on the uterus and breast. In ovariectomized rats, it has been shown to stimulate the beta-endorphin and allopregnanolone concentrations of the anterior and neurointermediate pituitary lobes, the hypothalamus and the hippocampus. The present study aimed to evaluate, in 12 healthy postmenopausal women, the effect of 60 mg/day raloxifene hydrochloride administration for 6 months on plasma beta-endorphin and allopregnanolone levels, and on the dynamic changes of both beta-endorphin and allopregnanolone secretion after the administration of: (1) clonidine, an alpha 2-presynaptic adrenergic agonist; (2) naloxone, an opioid receptor antagonist; and (3) fluoxetine, a serotonin selective reuptake inhibitor. The administration of raloxifene significantly increased both circulating beta-endorphin and allopregnanolone concentrations, at both the third and sixth months of treatment (p < 0.01). Clonidine, fluoxetine and naloxone administration before therapy was not able to stimulate the release of beta-endorphin, but the response was completely restored after raloxifene administration. Before therapy, clonidine and naloxone tests were accompanied by a significant rise in allopregnanolone secretion; the same changes were observed after raloxifene administration, but with significantly higher allopregnanolone concentrations at each time considered. While the fluoxetine test before therapy failed to increase the release of allopregnanolone, the same test after 6 months of raloxifene administration was characterized by a significant release of allopregnanolone at 60 and 90 minutes. The present data indicate that raloxifene has an estrogen-like effect on neuroendocrine pathways in postmenopausal women.

Adrenergic alpha-Agonists↗
PubMed2006

Estrogen-related receptors as emerging targets in cancer and metabolic disorders.

While estrogen receptor (ER)-targeted therapeutics have clearly been a success in the treatment of breast cancer, the orphan estrogen-related receptors (ERRs) represent novel targets for future development. The ERRs, comprising ERRalpha, ERRbeta and ERRgamma, bind and regulate transcription via estrogen response elements (EREs) and extended ERE half-sites termed ERR response elements (ERREs), but do not bind endogenous estrogens. The emerging role of ERRalpha and ERRgamma in modulating estrogen responsiveness, substituting for ER activities, and serving as prognosticators in breast and other cancers is providing an impetus for the identification of compounds which target these proteins. Moreover, ERRalpha plays a role in energy homeostasis and will likely be targeted for the treatment of metabolic disorders. Multiple classes of synthetic ligands have already been identified. The phytoestrogens genistein, daidzein, biochanin A and 6,3'4'-tryhydroxyflavone have been reported as ERRalpha agonists. The phenolic acyl hydrazones GSK4716 and GSK9089 act as selective agonists of ERRbeta and ERRgamma. The organochlorine pesticides toxaphene and chlordane, and the synthetic compound XCT790 antagonize ERRalpha. The synthetic estrogen diethylstilbestrol antagonizes all three ERRs. The selective estrogen receptor modulators 4-hydroxytamoxifen and 4-hydroxytoremifene antagonize ERRgamma. The rational development of synthetic ligands for the ERRs may soon provide new agents to supplement the repertoire of antihormonal therapies to combat breast cancer. Moreover, expression of ERRs in other cancers and metabolic disorders may provide a targeted treatment strategy for these patients as well.

Animals↗
PubMed2003

Identification of estrogen receptor beta expression in Chinese hamster ovary (CHO) cells and comparison of estrogen-responsive gene transcription in cells adapted to serum-free media.

Most cultured cell lines require addition of serum to the medium to maintain their proliferative capacity. For studies examining the cellular effects of estrogens serum is charcoal-stripped to remove steroids. Nonetheless, addition of the selective estrogen receptor modulator (SERM) 4-hydroxytamoxifen (4-OHT) inhibits the basal transcriptional activity of estrogen receptors alpha or beta (ERalpha or ERbeta) in transfected cells. We tested the hypothesis that elimination of serum from the culture medium will block 4-OHT's repression of basal activity. Chinese hamster ovary (CHO-K1) cells adapted to serum-free medium exhibited estrogen responsiveness that was identical with that of the cells grown in serum-containing media. 4-OHT-suppressed basal transcription of an estrogen response element (ERE)-reporter in ERalpha-transfected cells even in the absence of serum, indicating that the 4-OHT suppressive activity is not mediated by blocking ER interaction with serum estrogens. We speculate that 4-OHT-ER recruits co-repressors to suppress basal transcription. We discovered that CHO-K1 cells express ERalpha and ERbeta mRNA. However only ERbeta protein was expressed and use of ERbeta-selective 2,3-bis(4-hydroxy-phenyl)propionitrile (DPN) and ERalpha-selective 4-propyl-1,3,5-tris(4-hydroxy-phenyl)pyrazole) (PPT) revealed that only ERbeta was transcriptionally active. In conclusion, growing CHO-K1 in serum-free medium does not impact the estrogen responsiveness and this cell line expresses functional ERbeta.

Animals↗