Androgen receptor is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiologic ligands for androgen receptor ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit androgen receptor transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semisynthetic analogues (T2 and T3) revealed that these diterpenoids have antiandrogen properties that include inhibition of both androgen-dependent proliferation and androgen receptor transcriptional activity by a mechanism that involved competing with androgen for androgen receptor LBD and blocking essential N/C interactions required for androgen-induced androgen receptor transcriptional activity. Structure-activity relationship analyses revealed some chemical features of T1 that are associated with
Department of Urology, Mayo Graduate School, Mayo Foundation, Rochester, Minnesota, MN 55905, USA. Androgens via their cognate receptor may be involved in the development and progression of prostate cancer. The aim of this study was to determine whether tea polyphenols have inhibitory effects on androgen action in an androgen-responsive, prostate cancer cell line, LNCaP. The tea polyphenol, EGCG, inhibited LNCaP cell growth and the expression of androgen regulated PSA and hK2 genes. Moreover, EGCG had a significant inhibitory effect on the androgenic inducibility of the PSA promoter. Immunoblotting detected a decrease in androgen receptor protein with treatments of the tea polyphenols EGCG, GCG and theaflavins. Northern blot analysis showed decreased levels of androgen receptor mRNA by EGCG. Transient transfections demonstrated that EGCG and theaflavins could repress the transcriptional activities of the androgen receptor promoter region. An Sp1 binding site in the androgen receptor gene ...
TY - JOUR. T1 - Androgen receptor variants mediate DNA repair after prostate cancer irradiation. AU - Yin, Yi. AU - Li, Rui. AU - Xu, Kangling. AU - Ding, Sentai. AU - Li, Jeffrey. AU - Baek, Guem Hee. AU - Ramanand, Susmita G.. AU - Ding, Sam. AU - Liu, Zhao. AU - Gao, Yunpeng. AU - Kanchwala, Mohammed S.. AU - Li, Xiangyi. AU - Hutchinson, Ryan. AU - Liu, Xihui. AU - Woldu, Solomon L.. AU - Xing, Chao. AU - Desai, Neil B.. AU - Feng, Felix Y.. AU - Burma, Sandeep. AU - De Bono, Johann S.. AU - Dehm, Scott M.. AU - Mani, Ram S.. AU - Chen, Benjamin P.C.. AU - Raj, Ganesh V.. PY - 2017/9/15. Y1 - 2017/9/15. N2 - In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced ...
TY - JOUR. T1 - Drug Insight. T2 - Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. AU - Bhasin, Shalender. AU - Calof, Olga M.. AU - Storer, Thomas W.. AU - Lee, Martin L.. AU - Mazer, Norman A.. AU - Jasuja, Ravi. AU - Montori, Victor Manuel. AU - Gao, Wenqing. AU - Dalton, James T.. PY - 2006/3. Y1 - 2006/3. N2 - Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle ...
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of prostate cancer. When this compound was administered to ovariectomized mature female rats for 2 months researchers found it increased BMD and the biomechanical strength of cortical bone in the femur. These findings show that the effects of S-40503 on bone is applicable to both males and females. Rats treated with only estrogen a hormone used to prevent or minimize bone breakdown (resorption) did not positively affect BMD or cortical bone strength.. Please select the Card Type. Please enter a Security Code. LastName is required field.. When Cardarine is administered in excessively high doses in rats over a relatively long period of time the compound may cause cancer. SARMs and AASs. In the Mk-2866 Phytochemical Selective Androgen Receptor Modulator fitness community this compound is most commonly used to improve exercise endurance and assist in fat loss.. Exact Mass: 338. Molecular Weight: 338. Elemental Analysis: C 49. Shipped under ambient temperature as non-hazardous chemical. This product ...
In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized ...
TY - JOUR. T1 - A bifunctional colchicinoid that binds to the androgen receptor. AU - Sharifi, Nima. AU - Hame, Ernest. AU - Lill, Markus A.. AU - Risbood, Prabhakar. AU - Kane, Charles T.. AU - Hossain, Md Tafazzal. AU - Jones, Amanda. AU - Dalton, James T.. AU - Farrar, William L.. PY - 2007/8/1. Y1 - 2007/8/1. N2 - Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a Ki of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational ...
Conjugate inhibits androgen receptor transactivation and translocation in prostate cancer cells.Effect of conjugate on the transactivation of androgen receptor
Fibroblast growth factor signaling as a bypass mechanism of the androgen receptor pathway: new perspectives for castrationresistant prostate cancer
Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.
Non-steroidal compounds which are high affinity, high specificity ligand antagonists for the androgen receptor are disclosed. Also disclosed are methods for employing the disclosed compounds for modulating processes mediated by the androgen receptor and for treating patients requiring androgen receptor antagonist therapy.
TY - JOUR. T1 - RNA editing of androgen receptor gene transcripts in prostate cancer cells. AU - Martinez, Harryl D.. AU - Jasavala, Rohini J.. AU - Hinkson, Izumi. AU - Fitzgerald, Latricia D.. AU - Trimmer, James S.. AU - Kung, Hsing Jien. AU - Wright, Michael E.. PY - 2008/10/31. Y1 - 2008/10/31. N2 - Reactivation of the androgen receptor (AR) signaling pathway represents a critical step in the growth and survival of androgen-independent (AI) prostate cancer (CaP). In this study we show the DU145 and PC3 AI human CaP cell lines respond to androgens and require AR expression for optimal proliferation in vitro. Interestingly, AR gene transcripts in DU145 and PC3 cells harbored a large number of single base pair nucleotide transitions that resulted in missense mutations in selected AR codons. The most notable lesion detected in AR gene transcripts included the oncogenic codon 877T3→A gain-of-function mutation. Surprisingly, AR gene transcript nucleotide transitions were not genome-encoded ...
Taxane-based chemotherapy is an effective treatment for castration-resistant-prostate cancer (CRPC) via stabilization of microtubules. Previous studies identified that the inhibitory effect of microtubule-targeting chemotherapy on androgen receptor (AR) activity was conferred by interfering with AR …
Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so
Prostate cancer is a disease driven by the androgen receptor (1-4). Androgen receptor is a 110-kDa steroid receptor, which is sequestered in the cytoplasm by chaperones in the absence of its ligand. In the presence of dihydrotestosterone, androgen receptor dimerizes and enters the nucleus, where it binds to androgen response elements and activates transcription of responsive genes. One of the key challenges in prostate cancer research has been determining how androgen receptor functions in recurrent or androgen-independent prostate cancer (also called hormone-refractory prostate cancer; refs. 5-11) and how pharmacologic inhibitors affect function (12). Our groups have been addressing this problem using gene expression-based bioluminescence imaging to evaluate androgen receptor function in xenograft models (13-16), which accurately recreate prostate cancer progression from an androgen-dependent to an androgen-independent phase (17).. Imaging provides a means to probe the mechanism of cancer in ...
TY - JOUR. T1 - Androgen receptor rediscovered. T2 - The new biology and targeting the androgen receptor therapeutically. AU - Ryan, Charles J.. AU - Tindall, Donald J.. PY - 2011/9/20. Y1 - 2011/9/20. N2 - Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen-androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, ...
Translation of androgen receptor (AR) cRNA in a reticulocyte lysate and subsequent analysis of the translation products by SDS/PAGE showed a protein with an apparent molecular mass of 108 kDa. Scatchard-plot analysis revealed a single binding component with high affinity for R1881 (Kd = 0.3 nM). All AR molecules synthesized specifically bound steroid. No evidence for AR phosphorylation during in vitro synthesis was found. When AR was labelled with [3H]R1881 and analysed on sucrose-density gradients, a complex of approx. 6 S was observed. The complex was shifted to a higher sedimentation coefficient after incubation with a monoclonal AR antibody directed against an epitope in the DNA-binding domain. In the presence as well as the absence of hormone, AR molecules were able to bind to DNA-cellulose without an activation step. Gel retardation assays revealed that the AR forms complexes with a DNA element containing glucocorticoid-responsive element/androgen-responsive element sequences. Receptor-DNA ...
BioAssay record AID 353554 submitted by ChEMBL: Inhibition of DHT binding to human recombinant androgen receptor ligand binding domain at 15 uM by fluorescence polarization.
TRACK ORDERS RE-ORDER PRODUCTS AND MANAGE YOUR WISHLIST HERE. FIND OUT WHAT PAYMENT METHODS WE ACCEPT HERE ALONG WITH OUR ORDER POLICIES. INFORMATION ON OUR RETURN EXCHANGE AND REFUND POLICIES. Sarm S22 Review Gtx-024 permalink to DNA vs. You need to be a registered member to rate this post. Do SARMs or Selective Androgen Receptor Modulators build muscle? This guide contain everything you need to know. Simple Share Buttons Adder (6.. Wu D Wu Z Nair V Miller DD Dalton JT. Urinary metabolites of S-1 a novel selective androgen receptor modulator (sarm) in rats. Marhefka CA Sarm S22 Review Gtx-024 Moore BM 2nd Bishop TC Kirkovsky L Mukherjee A Dalton JT Miller DD. Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands. Bohl CE Chang C Mohler ML Chen J Miller DD Swaan PW Dalton JT.. Based on enobosarm ostarine and epistane these findings S-40503 appears to be an ideal ...
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METHOD OF TREATING ANDROGEN RECEPTOR (AR) -POSITIVE BREAST CANCERS WITH SELECTIVE ANDROGEN RECEPTOR MODULATOR (SARMS) - This invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods of: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from triple negative breast cancer; i) treating a subject suffering from advanced breast cancer; j) treating a subject suffering from breast cancer that has failed SERM (tamoxifen, toremifene), aromatase ...
Chronic inflammation is associated with advanced prostate cancer (PCa), although the mechanisms governing inflammation-mediated PCa progression are not fully understood. PCa progresses to an androgen independent phenotype that is incurable. We previously showed that androgen independent, androgen receptor negative (AR−) PCa cell lines have high p62/SQSTM1 levels required for cell survival. We also showed that factors in the HS-5 bone marrow stromal cell (BMSC) conditioned medium can upregulate p62 in AR+ PCa cell lines, leading us to investigate AR expression under those growth conditions. In this paper, mRNA, protein, and subcellular analyses reveal that HS-5 BMSC conditioned medium represses AR mRNA, protein, and nuclear accumulation in the C4-2 PCa cell line. Using published gene expression data, we identify the inflammatory cytokine, IL-1β, as a candidate BMSC paracrine factor to regulate AR expression and find that IL-1β is sufficient to both repress AR and upregulate p62 in multiple ...
BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full-length androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (,1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is ...
Background: The chemopreventive effects of resveratrol (RSV) on prostate cancer have been well established; the androgen receptor (AR) plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity. Methodology: The AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of ARnegative HeLa cells to generate the AR(+) cells. The constitutively expressed AR was characterized by monitoring hormonestimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(-) cells serving as controls. AR(+) cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP) assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE).
In particular, the scientists were studying the role the androgen receptor plays in prostate homeostasis by deleting the androgen receptor in luminal epithelial cells. The androgen receptor allows cells to respond to androgens, hormones that affect how the male reproductive system develops. Most prostate luminal epithelial cells need androgen to survive. Dihydrotestosterone is the most active androgen.. Although other research groups had already studied the role of androgen receptor in the prostate by deleting the receptor in prostate epithelial cells, Xin and colleagues were not satisfied with the results.. "There are two limitations to those previous studies," said Xin. "First, their approach was to delete the androgen receptor in the prostate at very early stages of the animals development, before puberty. Therefore, it is uncertain whether the outcomes of the experiment reflect the role of androgen receptor in development or the role in homeostasis. The second limitation is that the ...
Activity of SRs is not only regulated by ligand binding but also by interacting cofactors. The best-described binding site for SR coregulators is the hydrophobic cleft in the LBD to which LxxLL motifs can bind. The AR LBD is unique in its preference for the interaction with cofactors carrying FxxLF motifs rather than LxxLL motifs (Dubbink et al., 2004; Hur et al., 2004). The AR itself also contains an FQNLF motif in the N-terminal domain, enabling interaction with the LBD (N/C interaction; Doesburg et al., 1997; He et al., 2000). The potential competition between the AR N-terminal FQNLF motif and similar motifs in cofactors for interaction with the LBD raises questions regarding the role of the N/C interaction in orchestrating cofactor interactions. To study AR N/C interactions in living cells, we tagged the AR at the N and C termini with YFP and CFP, respectively, or with CFP alone, and applied FRET and simultaneous FRET and FRAP experiments. In addition, to investigate cofactor interactions, ...
TY - JOUR. T1 - A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. AU - Takeda, David Y.. AU - Spisák, S.. AU - Seo, Ji Heui. AU - Bell, Connor. AU - OConnor, Edward. AU - Korthauer, Keegan. AU - Ribli, Dezső. AU - Csabai, I.. AU - Solymosi, N.. AU - Szállási, Zoltán. AU - Stillman, David R.. AU - Cejas, Paloma. AU - Qiu, Xintao. AU - Long, Henry W.. AU - Tisza, Viktória. AU - Nuzzo, Pier Vitale. AU - Rohanizadegan, Mersedeh. AU - Pomerantz, Mark M.. AU - Hahn, William C.. AU - Freedman, Matthew L.. PY - 2018/1/1. Y1 - 2018/1/1. N2 - Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by ...
To develop and evaluate a new method for determination of the CAG repeat length in Exon 1 of the androgen receptor gene. DESIGN AND METHODS: The method is based on PCR amplification of a DNA region encompassing the repeats and analysis of the length of the PCR product on a sequencing gel. One of the PCR primers was labeled with Cy5.5 fluorescent dye to facilitate detection after laser excitation. We used a fully automated system for electrophoretic separation of the PCR product and accurate sizing of the length of the PCR product using fragment analysis. RESULTS: The major advantages of the new technique are its simplicity, speed, accuracy, and reproducibility. Analysis of the CAG repeats in genomic DNAs from 18 males indicated that they were all hemizygous with a mean CAG repeat number of 22 (range 20-30 repeats). Among 60 DNAs from females, 16 were homozygous and 44 were heterozygous. The repeat length ranged from 17-30 with a mean of 22. In both males and females, the distribution of CAG ...
Thank you for this information and the opportunity to reply. Unfortunately, the study of androgen receptor (AR) CAG repeats by Kasami and colleagues1 is not included in the usual searches and this appears to be the reason for overlooking this reference. In this study, cases of fibroadenoma, ductal carcinoma in situ (DCIS), and invasive mammary carcinoma were included. Twenty four cases of DCIS were tested for AR CAG repeats and 10 were tested for AR expression immunohistochemically. Two of 10 cases were positive for AR and these two cases were the only cases with apocrine morphology. However, in our study,2 we found that 19 of 57 cases of DCIS expressed AR. Thirteen of those 19 cases were of non-apocrine morphology. In addition, of the nine morphologically apocrine cases, three lacked AR expression. It seems to be that AR is expressed in a subset of DCIS even without apocrine morphology, but it is not necessarily true that all morphologically apocrine cases of DCIS will express AR. In Kasami and ...
A method was developed for measuring in vivo rates of mRNA synthesis in mice by pulse-labeling with the RNA precursor [3H]orotate and then using hybridization to recover specific mRNAs. The efficiency of recovery is determined with synthetic RNAs as internal hybridization standards. The method is particularly applicable to the kidney since this organ shows a strong preferential uptake of the label. Rates of synthesis, expressed as a fraction of total RNA synthesis, were measured for the androgen-inducible mRNAs coding for beta-glucuronidase (GUS), ornithine decarboxylase (ODC), the protein coded by the RP-2 gene, and the so-called kidney androgen-regulated protein (KAP). Control mRNAs coded for beta-actin, phosphoenolpyruvate carboxykinase, and major urinary protein. Testosterone markedly increased the synthesis of the androgen-inducible mRNAs, but not the control mRNAs. Induction was not seen in mutant mice lacking functional androgen receptor protein. For GUS, ODC, and RP-2 mRNAs, the
Alterations in transcriptional programs are fundamental to the development of cancers. The androgen receptor is central to the normal development of the prostate gland and to the development of prostate cancer. To a large extent this is believed to be due to the control of gene expression through the interaction of the androgen receptor with chromatin and subsequently with coregulators and the transcriptional machinery. Unbiased genome-wide studies have recently uncovered the recruitment sites that are gene-distal and intragenic rather than associated with proximal promoter regions. Whilst expression profiles from AR-positive primary prostate tumours and cell lines can directly relate to the AR cistrome in prostate cancer cells, this distribution raises significant challenges in making direct mechanistic connections. Furthermore, extrapolating from datasets assembled in one model to other model systems or clinical samples poses challenges if we are to use the AR-directed transcriptome to guide the
Hsing AW, Gao YT, Wu G., Wang X., Deng J., Chen YL, Sesterhenn IA, Mostofi FK, Benichou J., Chang C.. Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res. 2000;60: 5111-5116 ...
A low number of CAG repeats were independently associated with protective parameters (low body fat mass and plasma insulin) as well as with adverse parameters (low high density lipoprotein cholesterol concentrations). This suggests that the pivotal role of this polymorphism in modulating androgen ef …
The androgen receptor (AR) is a ligand-dependent transcription factor, expressed in male and female reproductive organs, and essential for normal reproduction in both sexes. The levels of AR are tightly controlled in androgen-responsive cells in which it plays a central role in the regulation of target gene expression. The AR is abundantly expressed in human endometrial stromal cells (HESCs), but levels decline markedly after differentiation into decidual cells in vivo and in primary cultures. Decidualization profoundly down-regulated AR protein levels with no discernible effect on either AR mRNA or protein stability, suggesting that loss of the receptor was a consequence of translational inhibition. Here we show that HESCs express three RNA-binding proteins, Hu antigen R and the poly(C)-binding proteins PCBP1 and PCBP2, that reportedly target the 3′-untranslated region of AR transcripts. Only PCBP1 expression was enhanced in secretory endometrium in vivo and in decidualizing HESCs. ...
Receptor tyrosine kinase HER2 has been previously shown to modulate AR signaling, in part, through its effect on the recruitment and binding of AR to the androgen-responsive enhancer elements (14, 15). Ligand-activated HER2 led to AR tyrosine phosphorylation, which was abrogated by Ack1 knockdown. Ack1 was tyrosine phosphorylated by heregulin treatment, and elimination of surface HER2 expression abolished heregulin-dependent tyrosine phosphorylation of Ack1. These results suggest that Ack1 is a critical intermediate of HER2 signaling in prostate cancer cells and its activation of AR-regulated genes (13). The effect of Ack1 knockdown on androgen target gene expression such as PSA and hK2 and recruitment and DNA binding of AR is similar to the reported effect of HER2 inhibition or knockdown (14, 15). Cells expressing activated Ack1 exhibit enhanced recruitment and DNA binding of AR and increased androgen target gene expression. These data are consistent with the hypothesis that Ack1 is a ...
Doping control authorities and sports drug testing laboratories are frequently confronted with the illicit use of performance-enhancing therapeutics and therefore various analytical strategies have been developed to detect a misused drug and/or its metabolic product(s) in blood or urine specimens. Besides the administration of clinically approved drugs prohibited in sports,
Ligands findings suggest the potential for LGD-3303 to be useful either as a single agent or in combination with conventional bisphosphonate therapy. The data suggest that LGD-3303 may provide a safe and effective new drug for the treatment of osteoporosis, including in patients that have had an inadequate response to bisphosphonate treatment.. SARM Program. Ligand has conducted extensive drug research with SARMs. In its research collaboration with TAP Pharmaceutical Products, Ligand discovered the SARM LGD-2941, which TAP is developing in a Phase I clinical trial. Ligand has rights to several SARM molecules. In addition to LGD-3303, Ligand is formulating and optimizing a library of SARM compounds to potentially advance to clinical development.. About Ligand Pharmaceuticals. Ligand discovers and develops new drugs that address critical unmet medical needs of patients in the areas of thrombocytopenia, hepatitis C, cancer, hormone-related diseases, osteoporosis and inflammatory diseases. Ligands ...
The aim of this study is to determine the effect of enobosarm, a selective androgen receptor modulator, using a "window of opportunity study" in women
Androgen Receptor (Marker of Androgen Dependence) Antibody, Mouse Monoclonal Antibody [Clone DHTR/882 ] validated in IHC, IF, FC (AH11597-7), Abgent
Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin-signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in ...
Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor ligands. They are intended to exhibit the same kind of effects as androgenic drugs, like anabolic steroids, but be much more selective in their action, targeting particular tissues without any undesirable effects on others. While the main applications of these synthetic substances are for therapeutic purposes, they also have a high potential for misuse in veterinary practice and the sporting world. In order to guarantee for consumers with food from animal origin that it is free from any residues of such compounds, analytical strategies are required to ensure safe food and also to enable fair trade between producers ...
Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions: Structural changes in the
LGD-4033 is an ideal testosterone enhancing supplement that operates as selective androgen receptor modulator (SARM). Bodybuilders use it as an alternative to steroids that are known to cause many side effects. When taken at the recommended dosage, the product has proven to attract considerable lean mass gain after a short period.. How LGD-4033 works. The ligandrol is a very effective, powerful, and safe testosterone enhancer that works by binding to certain selective androgen receptors in your muscles to deliver quick and excellent results. Other androgens are mostly found in the brain, fat, and bones.. Also, the supplement contains special elements for the legitimate medical drug. This makes it suitable for treating conditions like muscular dystrophy or wasted muscles. The supplement is, therefore, widely used for boosting performance due to its ability to speed up the production of testosterone in the body. By producing this hormone, it helps the body produce more energy as it increases its ...
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The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an
in Trabajos del Instituto Cajal (2009), LXXXII. Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent ... [more ▼]. Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelching, between two different nuclear receptors introduced the notion that common cofactors might be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors, which are now known as coactivators, are involved in chromatin remodeling and stabilization of the general transcription machinery. Since the characterization of ...
The present study represents the first to demonstrate PPD as an effective agent to downregulate the expression and activity of both the full-length AR and the AR-Vs in prostate cancer. This report is also the first to show the in vivo efficacy of PPD against AR-expressing prostate cancer cells, which constitute the majority of clinical prostate carcinomas. We further show that PPD suppression of tumor growth is accompanied by a considerable decline in AR expression in prostate tumor xenografts and PSA levels in the serum. The decline in serum PSA levels is not simply a consequence of reduction of tumor sizes by PPD, as the effect remains pronounced after normalization by tumor weight. The data instead indicate the ability of PPD to suppress AR activity in the tumors.. Despite its structural similarity with androgens, PPD has limited ability to compete with androgens for binding to AR. Instead, the effect of PPD on AR is manifested by an immediate drop in protein, followed by a reduction in mRNA. ...
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named "ligand dependent transcription factors." R.M. Evans, Science, 240:889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR) androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand, which has the ability to selectively bind to the IR in a way that affects gene transcription ...