scholarly journals Selective androgen receptor modulators (SARMs) have specific impacts on the mouse uterus

2019 ◽  
Vol 242 (3) ◽  
pp. 227-239 ◽  
Author(s):  
Ioannis Simitsidellis ◽  
Arantza Esnal-Zuffiaure ◽  
Olympia Kelepouri ◽  
Elisabeth O’Flaherty ◽  
Douglas A Gibson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Muscle Wasting ◽  
Tissue Architecture ◽  
Mouse Uterus ◽  
Minimal Impact ◽  
Selective Androgen Receptor Modulators ◽  
The Impact ◽  
Receptor Modulators

Selective androgen receptor modulators (SARMs) have been proposed as therapeutics for women suffering from breast cancer, muscle wasting or urinary incontinence. The androgen receptor (AR) is expressed in the uterus but the impact of SARMs on the function of this organ is unknown. We used a mouse model to compare the impact of SARMs (GTx-007/Andarine®, GTx-024/Enobosarm®), Danazol (a synthetic androstane steroid) and dihydrotestosterone (DHT) on tissue architecture, cell proliferation and gene expression. Ovariectomised mice were treated daily for 7 days with compound or vehicle control (VC). Uterine morphometric characteristics were quantified using high-throughput image analysis (StrataQuest; TissueGnostics), protein and gene expression were evaluated by immunohistochemistry and RT-qPCR, respectively. Treatment with GTx-024, Danazol or DHT induced significant increases in body weight, uterine weight and the surface area of the endometrial stromal and epithelial compartments compared to VC. Treatment with GTx-007 had no impact on these parameters. GTx-024, Danazol and DHT all significantly increased the percentage of Ki67-positive cells in the stroma, but only GTx-024 had an impact on epithelial cell proliferation. GTx-007 significantly increased uterine expression of Wnt4 and Wnt7a, whereas GTx-024 and Danazol decreased their expression. In summary, the impact of GTx-024 and Danazol on uterine cells mirrored that of DHT, whereas GTx-007 had minimal impact on the tested parameters. This study has identified endpoints that have revealed differences in the effects of SARMs on uterine tissue and provides a template for preclinical studies comparing the impact of compounds targeting the AR on endometrial function.

scholarly journals Selective androgen receptor modulators in preclinical and clinical development

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06010 ◽  
Author(s):  
Ramesh Narayanan ◽  
Michael L. Mohler ◽  
Casey E. Bohl ◽  
Duane D. Miller ◽  
James T. Dalton
Keyword(s):  
Androgen Receptor ◽  
Muscle Wasting ◽  
Anabolic Steroids ◽  
Critical Role ◽  
Growth Effect ◽  
Anabolic Activity ◽  
Selective Androgen Receptor Modulators ◽  
Stage Renal Disease ◽  
End Stage ◽  
Receptor Modulators

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

scholarly journals Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor Modulators

2006 ◽  
Vol 20 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Dmitri Kazmin ◽  
Tatiana Prytkova ◽  
C. Edgar Cook ◽  
Russell Wolfinger ◽  
Tzu-Ming Chu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Rational Design ◽  
Dynamic Structure ◽  
Rational Approach ◽  
Peptide Phage Display ◽  
Differential Gene ◽  
Receptor Modulators ◽  
Kinetics Of

Abstract We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.

scholarly journals Anatomic Origin of Osteochondrogenic Progenitors Impacts Sensitivity to EWS-FLI1-Induced Transformation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 313 ◽  
Author(s):  
Elise Pfaltzgraff ◽  
April Apfelbaum ◽  
Andrew Kassa ◽  
Jane Song ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Progenitor Cells ◽  
Malignant Transformation ◽  
Ewing Sarcoma ◽  
Hox Genes ◽  
High Expression ◽  
Wild Type ◽  
Superficial Zone ◽  
The Impact

Ewing sarcomas predominantly arise in pelvic and stylopod bones (i.e., femur and humerus), likely as a consequence of EWS-FLI1 oncogene-induced transformation of mesenchymal stem/progenitor cells (MSCs). MSCs located in the embryonic superficial zone cells (eSZ) of limbs express anatomically distinct posterior Hox genes. Significantly, high expression of posterior HOXD genes, especially HOXD13, is a hallmark of Ewing sarcoma. These data drove our hypothesis that Hox genes in posterior skeleton MSCs contribute to Ewing sarcoma tumorigenesis. We isolated eSZ cells from stylopod and zeugopod (i.e., tibia/fibula, radius/ulna) bones, from wild-type and Hoxd13 mutant embryos, and tested the impact of EWS-FLI1 transduction on cell proliferation, gene expression, and tumorigenicity. Our data demonstrate that both stylopod and zeugopod eSZ cells tolerate EWS-FLI1 but that stylopod eSZ cells are relatively more susceptible, demonstrating changes in proliferation and gene expression consistent with initiation of malignant transformation. Significantly, loss of Hoxd13 had no impact, showing that it is dispensable for the initiation of EWS-FLI1-induced transformation in mouse MSCs. These findings show that MSCs from anatomically distinct sites are differentially susceptible to EWS-FLI1-induced transformation, supporting the premise that the dominant presentation of Ewing sarcoma in pelvic and stylopod bones is attributable to anatomically-defined differences in MSCs.

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