Effects Of Selective Estrogen Receptor Modulators Research Articles

Design, synthesis, and in-silico study of novel triarylethylene analogs with dual anti-estrogenic and serotonergic activity.

Estrogen receptor is an important target in breast cancer. Serotonin receptors (5-HT2A and 5-HT2C , in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative β- galactosidase activity = 0.70), 5-HT2A (Ki = 0.97 µM), and 5-HT2C (Ki = 3.86 µM). It was more potent on both MCF-7 (GI50 = 0.27 µM) and on MDA-MB-231 (GI50 = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF-7 and 15 times on MDA-MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in-silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5-HT2A , and 5-HT2C .

Effectiveness of Selective Estrogen Receptor Modulators in Breast Cancer Therapy: An Update.

Breast cancer is considered to be 2nd most common cancer subtype investigated worldwide. It is mainly prevalent in postmenopausal women. Estrogen Receptor (ER) is a primary transcription factor for the survival and growth of tumors. Around 80% BCs of all classes are ER-positive (ER+). Powerful evidence for estrogen proved to be involved in BC pathogenesis both exogenously and endogenously. It brings the concept of ER inhibitors to treat BC with distinct mechanisms into focus and ER PROTACs (Proteolysis-Targeting Chimeras), AIs (Aromatase inhibitors), SERMs (Selective estrogen receptor modulators), and SERDs (Selective estrogen receptor degrader) were developed. For over 30 years, Tamoxifen, a triphenylethylene SERM, was the drug of choice solely to treat ER+BC patients. Although several SERMs got approval by US FDA after tamoxifen, complicacies remain because of dangerous adverse effects like endometrial carcinoma, hot flashes, and VTE (Venous thromboembolism). In addition to that, drug-resistant tumors put a surging need for novel, potent candidates with no or low adverse effects for ER+ BC prevention. This article explores the possibilities of SERMs as effective BC agents. A detailed literature survey of the history and recent advancements of SERMs has been carried out, taking BC as the primary target. This review provides information about ER structure, signaling, pharmacological action, chemical classification with SAR analysis, and benefits and adverse effects of SERMs as potential BC agents. Exhaustive literature studies suggested that SERMs having an agonistic, antagonistic or mixed activity to ER could efficiently inhibit BC cell proliferation. Each chemical class of SERMs comprises some salient features and potentials, which may be further investigated to obtain novel effective SERMs in BC therapy.

Hormone therapy for sexual function in perimenopausal and postmenopausal women.

Hormone therapy for sexual function in perimenopausal and postmenopausal women.

Selective Estrogen Receptor Modulators (SERMs) Synergize with Cisplatin, Induce Apoptosis and Suppress Cellular Migration and Colony Formation of Lung Cancer Cells.

Lung cancer remains the leading cause of cancer-related deaths worldwide. Hence, novel therapeutic approaches targeting crucial pathways are needed to improve its treatment. Previous studies have verified the involvement of the estrogen pathway, mediated through estrogen receptor β (ERβ), in the development and progression of lung carcinogenesis. Selective estrogen receptor modulators (SERMs) are a group of estrogen receptor agonists/antagonists that have tissue selective effects. Many of the available SERMs are used for the management of breast cancer. However, their role in lung cancer is still under investigation. The aim of this research is to investigate the anti-tumorigenic activity of the selective estrogen receptor modulators, tamoxifen, raloxifene, and toremifene, against different lung cancer cell lines. The anti-proliferative and combined effects of SERMs with standard chemotherapy were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. Cells' capability to form colonies was evaluated by soft agar colony formation assay. Estrogen receptors expression was determined using real-time PCR. Our results have demonstrated the presence of ERβ in A549, H1299, and H661 lung cancer cells. Cellular proliferation assay suggested that SERMs have significantly reduced lung cancer cells proliferation in a time and concentration- dependent manner. Additionally, SERMs exhibited a synergistic effect against A549 cells when combined with cisplatin. SERMs treatment have increased cell apoptosis and resulted in concentration-dependent inhibition of cell migration and colony formation of A549 cells. Selective estrogen receptor modulators may possess potential therapeutic utility for the treatment of lung cancer as monotherapy or in combination with standard chemotherapy.

Estrogen and Estrogen Receptor Modulators: Potential Therapeutic Strategies for COVID-19 and Breast Cancer

Owing to the ongoing coronavirus disease 2019 (COVID-19) pandemic, we need to pay a particular focus on the impact of coronavirus infection on breast cancer patients. Approximately 70% of breast cancer patients express estrogen receptor (ER), and intervention therapy for ER has been the primary treatment strategy to prevent the development and metastasis of breast cancer. Recent studies have suggested that selective estrogen receptor modulators (SERMs) are a potential therapeutic strategy for COVID-19. With its anti-ER and anti-viral combined functions, SERMs may be an effective treatment for COVID-19 in patients with breast cancer. In this review, we explore the latent effect of SERMs, especially tamoxifen, and the mechanism between ER and virus susceptibility.

A tissue-specific role of membrane-initiated ERα signaling for the effects of SERMs.

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To determine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradiol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mERα-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were absent in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in the skeleton are mERα-dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrating mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mERα signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manner. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.

Selective oestrogen receptor modulators (SERMs) for endometriosis.

Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. This chronic and recurring condition occurs in women of reproductive age. It is a common cause of pain or infertility and can cause non-specific symptoms such as lower back pain, dyspareunia (pain during or after intercourse), and dysmenorrhoea (menstrual pain). Endometriosis is an oestrogen-dependent disease. Medical treatment aims to relieve symptoms and shrink lesions by suppressing the normal menstrual cycle. In this review, we consider medication specifically aiming to modulate oestrogen receptors as an alternative method of treatment. To evaluate the effectiveness and safety of selective oestrogen receptor modulators (SERMs) in the management of endometriosis. We searched for trials in the following databases (from their inception to 28 May 2020): Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies (CRS Online), MEDLINE, Embase, CINAHL, PsycINFO, and registers of ongoing trials. In addition, we searched all reference lists of included trials, and we contacted experts in the field, in an attempt to locate trials. We included randomised controlled trials (RCTs) comparing selective oestrogen receptor modulators (SERMs)with placebo, no treatment, other medical treatment, or surgery for endometriosis. We used standard methodological procedures recommended by Cochrane. Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted data using data extraction forms. We used risk ratios (RRs) with 95% confidence intervals (CIs) for reporting dichotomous data. Primary review outcomes were relief of pelvic pain and adverse events. Secondary outcomes included quality of life, recurrence rate, and economic and fertility outcomes. We included only one RCT, which included 93 women, comparing the SERM raloxifene with placebo in biopsy-proven endometriosis. Allwomen first underwentcomplete surgical excision of all lesions. Evidence was of very low quality: the main limitation was imprecision - with very sparse data from only one small study, which included only women after surgical treatment. Relief of pelvic pain The included study did not specifically measure the primary outcome of pain relief. Study authors reported that time to return of pelvic pain (defined as two months of pain equal to or more severe than pain at study entry) was more rapid in the raloxifene group (P = 0.03). Adverse events The included study reported adverse events such as pelvic pain, ovarian cyst, headache, migraine, and depression. We are uncertain whether raloxifene improves the incidence of pelvic pain (RR 1.25, 95% CI 0.63 to 2.45), ovarian cysts (RR 1.57, 95% CI 0.55 to 4.43), headache (RR 1.09, 95% CI 0.49 to 2.43), migraine (RR 0.73, 95% CI 0.28 to 1.95), depression (RR 1.96, 95% CI 0.63 to 6.06), or other adverse events (RR 0.08, 95% CI 0.00 to 1.30) (all: 1 study, n = 93; very low-quality evidence). Quality of life The study describeda statistically significant difference in mental health quality of life(QoL) by 12 months, in favour of placebo treatment (mean difference 11.1, 95% CI 0.01 to 21.19). Other QoL data did not differ between groups but were not reported in detail. Recurrence rate, fertility, and economic outcomes We are uncertain whether raloxifene improves the recurrence rate of endometriosis,proven by biopsy, when compared to placebo (RR 1.20, 95% CI 0.66 to 2.21; 1 study, n = 93; very low-quality evidence). Thissuggests that if 28% of women taking placebo have biopsy-proven recurrence of endometriosis, between 19% and 62% of those taking raloxifene will do so. These outcomes are prone to bias, as not all women had an actual second laparoscopy. Recurrence based on symptoms (non-menstrual pain, dysmenorrhoea, or dyspareunia) was described; in these cases, symptoms improved after use of raloxifene as well as after use of placebo. The included study did not report data on economic outcomes. No comparative data were available on pregnancy, as the study included only women who agreed to postpone pregnancy until after the study endpoint; the few pregnancies that did occur were uneventful but were regarded as an adverse event. AUTHORS' CONCLUSIONS: Based on a single, small RCT and incomplete data, we are uncertain of the effects of SERMs on pain relief in surgically treated patients with endometriosis. The included study was stopped prematurely because of higher pain scores among women who took SERMs when compared to scores among those receiving placebo. Further research is needed to fully evaluate the role of SERMs in endometriosis.

A Novel Mouse Model for SNP in Steroid Receptor Co-Activator-1 Reveals Role in Bone Density and Breast Cancer Metastasis.

The steroid receptor coactivator-1 (SRC-1) is a nuclear receptor co-activator, known to play key roles in both estrogen response in bone and in breast cancer metastases. We previously demonstrated that the P1272S single nucleotide polymorphism (SNP; P1272S; rs1804645) in SRC-1 decreases the activity of estrogen receptor in the presence of selective estrogen receptor modulators (SERMs) and that it is associated with a decrease in bone mineral density (BMD) after tamoxifen therapy, suggesting it may disrupt the agonist action of tamoxifen. Given such dual roles of SRC-1 in the bone microenvironment and in tumor cell-intrinsic phenotypes, we hypothesized that SRC-1 and a naturally occurring genetic variant, P1272S, may promote breast cancer bone metastases. We developed a syngeneic, knock-in mouse model to study if the SRC-1 SNP is critical for normal bone homeostasis and bone metastasis. Our data surprisingly reveal that the homozygous SRC-1 SNP knock-in increases tamoxifen-induced bone protection after ovariectomy. The presence of the SRC-1 SNP in mammary glands resulted in decreased expression levels of SRC-1 and reduced tumor burden after orthotopic injection of breast cancer cells not bearing the SRC-1 SNP, but increased metastases to the lungs in our syngeneic mouse model. Interestingly, the P1272S SNP identified in a small, exploratory cohort of bone metastases from breast cancer patients was significantly associated with earlier development of bone metastasis. This study demonstrates the importance of the P1272S SNP in both the effect of SERMs on BMD and the development of tumor in the bone.

Water extract of Er-xian decoction selectively exerts estrogenic activities and interacts with SERMs in estrogen-sensitive tissues

Ethnopharmacological relevanceThe increasing use of “kidney”-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. Aim of the studyThe present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). Materials and methodsIn vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. ResultsIn OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. ConclusionsEXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.

Role of cholesterol metabolism in the anticancer pharmacology of selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) are a class of compounds that bind to estrogen receptors (ERs) and possess estrogen agonist or antagonist actions in different tissues. As such, they are widely used drugs. For instance, tamoxifen, the most prescribed SERM, is used to treat ERα-positive breast cancer. Aside from their therapeutic targets, SERMs have the capacity to broadly affect cellular cholesterol metabolism and handling, mainly through ER-independent mechanisms. Cholesterol metabolism reprogramming is crucial to meet the needs of cancer cells, and different key processes involved in cholesterol homeostasis have been associated with cancer progression. Therefore, the effects of SERMs on cholesterol homeostasis may be relevant to carcinogenesis, either by contributing to the anticancer efficacy of these compounds or, conversely, by promoting resistance to treatment. Understanding these aspects of SERMs actions could help to design more efficacious therapies. Herein we review the effects of SERMs on cellular cholesterol metabolism and handling and discuss their potential in anticancer pharmacology.

Perioperative Use of Antiestrogen Therapies in Breast Reconstruction: A Systematic Review and Treatment Recommendations.

Patients with hormone receptor-positive breast tumors receive hormonal therapy with either selective estrogen receptor modulators (SERMs) (eg, tamoxifen) or aromatase inhibitors (AIs) (eg, anastrozole) for 5 to 10 years. Patients are using these therapies frequently during breast reconstruction. Literature investigating the effects of hormonal modulators on breast reconstruction outcomes demonstrates conflicting results. We sought to perform a systematic evaluation to assess the effects of hormonal therapy on breast reconstruction outcomes and to guide perioperative management of antiestrogen therapies. A MEDLINE, PubMed, and EBSCO Host search of articles regarding the effects of SERMs and AIs on breast reconstruction was performed. Outcomes evaluated included wound complications, total or partial flap loss, and thromboembolic events. Included studies were assigned Methodological Index for Nonrandomized Studies quality scores. A total of 2581 flaps were analyzed for complete loss: patients taking SERMs at the time of reconstruction had higher rates of flap loss compared with patients not taking hormone modulators (P < 0.001). Flap loss was not affected by concurrent AI use (P = 0.11). Both SERMs and AIs had an increased risk of donor site complications (P = 0.0021 and P < 0.0001, respectively). Neither hormone modulator had an effect on flap wound complications or venous thromboembolic event rates. Evidence indicates patients using SERMs at the time of operation are at an increased risk of flap loss and those taking either SERMs or AIs have higher rates of donor site complications. These findings support holding these medications for 1 to 2 half lives (tamoxifen, 14-28 days; AIs, 2-4 days) preoperatively.

Abstract A43: Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing

Abstract 1 in 8 women will be diagnosed with breast cancer within their lifetime. The majority of women are diagnosed with estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or HER2+ breast cancers. The standard of care for ER+ breast cancer is treatment with selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) drugs. While these are highly effective for ER+ breast cancers and additional targeted drugs exist for PR+ and HER2+ cancers, there are currently no targeted therapeutic strategies for the 10-15% of women who are diagnosed with triple-negative breast cancer (TNBC). We hypothesize that estrogen receptor-targeting drugs are capable of inducing phenotypic changes to sensitize breast tumor cells to immune-mediated killing regardless of their ER status. In this study, we used in vitro killing assays and molecular characterization of ER+ and ER- cell lines to identify that SERM and SERD drugs sensitize breast cancer to killing by healthy-donor natural killer (NK) cells regardless of their ER status. While tamoxifen (SERM) and fulvestrant (SERD) had no cytotoxic or antiproliferative effect on ER- cells, pretreatment with either resulted in increased NK-mediated cell lysis. Through RNAseq analysis of tamoxifen-treated ER+ and ER- cells, we identified increased activation of both apoptotic and death receptor signaling pathways. These pathways play a key role in immunogenic modulation, indicating a potential mechanism for tamoxifen-induced tumor sensitization to immune cell lysis. It has previously been reported that in addition to binding to ER, both tamoxifen and fulvestrant bind to G protein-coupled estrogen receptor 1 (GPR30). We found that GPR30 is expressed in both ER+ and ER- breast cancer cells. Using the specific GPR30 agonist G-1, we demonstrated that targeted activation of GPR30 signaling resulted in increased NK cell killing. These data indicate that the observed ER-independent immunogenic modulation of breast cancer cells may be occurring through GPR30. Together, these findings demonstrate a novel effect of SERM and SERD drugs on the interaction between both ER+ and ER- tumor cells with the immune system. This study is the first to demonstrate the potential use of ER-targeting drugs in immunotherapy combinations in an ER-agnostic manner and may inform novel immunotherapy strategies in breast cancer. Citation Format: Benjamin Wolfson, Jeffrey Schlom, James Hodge. Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A43.

Selective Estrogen Receptor Modulators (SERMs): Mechanistic Insights Against Microbial Infections.

Infections are one of the leading causes of death worldwide and currently available treatments remain unsatisfactory due to rise in the cases of antimicrobial resistance. Thus, there is a need for the development of new drugs with different mechanisms of action. However, the development of new antimicrobials agents is a long and expensive process. Hence, most of the pharmaceutical companies are looking forward to repurposing the already available drugs against microbial infections. The data related to SERMs and microbial infection has been extracted from Pub Med (from January 1997 to December 2018). A total of 101 studies have been published from 1997 -2018 regarding SERMs and microbial infections. On the basis of inclusion and exclusion criteria, 25 studies have been included for the analysis of level of evidence regarding antimicrobial effects of SERMs. Emerging reports have indicated the antimicrobial property of selective estrogen receptor modulators (SERMs) against normal and resistant strains under in vitro and in vivo conditions against wide variety of microorganisms through different mechanisms of action. In conclusion, SERMs could be developed as a broad spectrum antimicrobial agent alone or in combination with existing antimicrobial agents.

Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?

Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11-256) and follow-up time was relatively short (6weeks to 12months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long-term safety profile.

In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues.

Tamoxifen, raloxifene, and nafoxidine are selective estrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogs was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene > bazedoxifene ∼ lasofoxifene > tamoxifen > acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular-docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular-docking analyses provide new insights into the interaction between SERMs and AOX1. SIGNIFICANCE STATEMENT: Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective estrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular- docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals.

Effects of the selective estrogen receptor modulators for the treatment of male infertility: a systematic review and meta-analysis

ABSTRACTBackground: Selective estrogen receptor modulators (SERMs) represent a poorly investigated class of drugs for the treatment of male infertility. The aim of this study was to assess the effects of SERMs on conventional sperm parameters, serum gonadotropin and testosterone levels, and pregnancy rate in patients with idiopathic infertility.Methods: The authors performed a comprehensive systematic review with meta-analysis of all available controlled and not-controlled studies of the literature reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate following SERM administration in normogonadotropic patients with idiopathic oligozoospermia.Results: From the 418 papers retrieved, 16 controlled and not-controlled trials were lastly included. SERM administration increased significantly sperm concentration, total sperm count, and serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels compared with baseline values. In contrast, SERMs did not have any significant effect on sperm concentration and progressive and total motility, but improved total sperm count, sperm morphology, and increased the pregnancy rate compared to the control group, which included studies done with placebo or other treatments.Conclusions: The results of this meta-analysis suggest that SERMs may be effective in the treatment of infertile patients with idiopathic infertility. However, the paucity of data does not allow to draw a definitive conclusion.

Future Aspects for Cannabinoids in Breast Cancer Therapy.

Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.

The tamoxifen derivative ridaifen-B is a high affinity selective CB2 receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects

Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the “ridaifen” compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity. Tamoxifen and other SERMs bind to cannabinoid receptors with moderate affinity. Therefore, ER-independent effects of SERMs might be mediated via cannabinoid receptors. This study determined whether RID-B, a first generation ridaifen compound, exhibits affinity and/or activity at CB1 and/or CB2 cannabinoid receptors. RID-B binds with high affinity (Ki = 43.7 nM) and 17-fold selectivity to CB2 over CB1 receptors. RID-B acts as an inverse agonist at CB2 receptors, modulating G-protein and adenylyl cyclase activity with potency values predicted by CB2 affinity. Characteristic of an antagonist, RID-B co-incubation produces a parallel-rightward shift in the concentration-effect curve of CB2 agonist WIN-55,212-2 to inhibit adenylyl cyclase activity. CB2 inverse agonists are reported to exhibit anti-inflammatory and anti-ostoeclastogenic effects. In LPS-activated macrophages, RID-B exhibits anti-inflammatory effects by reducing levels of nitric oxide (NO), IL-6 and IL-1α, but not TNFα. Only reduction of NO concentration by RID-B is mediated by cannabinoid receptors. RID-B also exhibits pronounced anti-osteoclastogenic effects, reducing the number of osteoclasts differentiating from primary bone marrow macrophages in a cannabinoid receptor-dependent manner. In summary, the tamoxifen derivative RID-B, developed with reduced affinity for ERs, is a high affinity selective CB2 inverse agonist with anti-inflammatory and anti-osteoclastogenic properties.

The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen improve ANP levels and decrease nuclear translocation of NF-kB in estrogen-deficient rats.

The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen-deficient rats has not been reported. We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-β-estradiol (E), OVX-treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days. Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-β-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions. Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women.

Abstract 320: Selective Estrogen Receptor Modulator Retards Arterial Senescence and Atherosclerosis via Upregulation of Sirt-1 and Autophagy in Post-menopause Model Mouse

Background: Incidence of cardiovascular disease (CVD) increases with development of arterial senescence and atherosclerosis, which are accelerated after menopause in women. This study aims 1) to clarify the mechanism of which post-menopose facilitates arterial senescence and atherosclerosis, and 2) to develop optical treatment. Methods and results: Female Apolipoprotein E deficient (ApoE KO) mice underwent ovariectomy at 8 weeks old were used as post-menopausal model mice (PM). Age-matched female mice with sham operation were used as control (Ctr). We confirmed that serum estrogen concentration was significantly lower in PM than in Ctr. Twelve weeks after surgery, aortas were harvested to examine molecular biological analysis. Sirt-1 and the ratio of LC3II/LC3I protein expressions were significantly lower in PM than in Ctr. Ratio of senescence associated β galactosidase (SA-β Gal) positive cells and expressions of acetyl (Ac)-p53, p21, and PAI-1 were significantly higher in PM than in Ctr. Aortic atherosclerotic lesions assessed by Oil Red O staining was significantly greater in PM than in Ctr. Overexpression of either Sirt-1 or autophagy retarded arterial senescence in vitro. These results suggest that ovariectomy accelerates arterial senescence and atherosclerotic development through downregulation of Sirt-1 and autophagy. Next, we administrated selective estrogen receptor modulator (SERM) to PM mice. Sirt-1 and the ratio of LC3II/LC3I protein expression were significantly higher in SERM-treated PM mice than in untreated mice. Ratio of SA-β Gal positive cells, protein expressions of Ac-p53, p21, and PAI-1, and aortic atherosclerotic lesions were significantly lower in SERM-treated PM mice than in untreated mice. The effect of SERM on augmentation of autophagy and inhibition of arterial senescence and atherosclerotic development was attenuated by administration of sirtinol, Sirt-1 inhibitor. Conclusion: SERM retards development of arterial senescence and atherosclerosis by activation of Sirt-1 and autophagy in postmenopause mice.