Anti‐androgenic effects of S‐40542, a novel non‐steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia

Nejishima, Hiroaki; Yamamoto, Norio; Suzuki, Mika; Furuya, Kazuyuki; Nagata, Naoto; Yamada, Shizuo

doi:10.1002/pros.22511

Cited by 21 publications

(19 citation statements)

References 21 publications

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“…as well (36). In our study, levels of AR were markedly elevated in TE-treated prostates and decreased after treatment with GRP antagonist RC-3940-II.…”

Section: Discussionsupporting

confidence: 59%

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dosedependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.bombesin | cell volume measurement | prostatic inflammation | rodent benign prostatic hyperplasia model | targeted therapy H ormonal polypeptides, bombesin (BN) and gastrin-releasing peptide (GRP), can act as autocrine and paracrine growth factors, and regulate cellular growth, differentiation, and apoptosis (1, 2). Tetradecapeptide bombesin was isolated from the skin of the European fire-bellied toad (Bombina bombina) (3), and subsequently, two mammalian bombesin-like peptides were characterized: GRP and neuromedin B (NMB) (4). GRP and BN influence the secretion of gastrointestinal hormones, stimulate the release of gastrin and somatostatin, induce pancreatic exocrine secretion (5), and induce contractions of the smooth muscle of the stomach, gall bladder, uterus, urinary bladder, and prostate (6). GRP was first shown to be a mitogen for Swiss 3T3 murine embryonal fibroblasts and, subsequently, for a number of normal cell types and cancers in vivo and in cell culture (7). GRP is now recognized as the prototypical autocrine growth factor, based on the detection of GRP and its receptors in small cell lung carcinoma and other tumors (8). GRP was shown to stimulate growth of several other types of carcinomas including those of prostate, breast, colon, and pancreas (9). Three different receptor subtypes for the BN/GRP family of peptides have been described in mammals (10). Receptor subtype 1 (termed GRP-R or BB 2 ) binds BN, GRP, and GRP antagonist RC-3940-II with high affinity (11). ...

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“…as well (36). In our study, levels of AR were markedly elevated in TE-treated prostates and decreased after treatment with GRP antagonist RC-3940-II.…”

Section: Discussionsupporting

confidence: 59%

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…49 In primary cultured and PrSC stromal cell lines, stromal AR might play positive roles to promote epithelial cell growth, and targeting AR signals in stromal cells can suppress the growth of BPH cells, suggesting that AR in stromal cells may play positive roles to promote BPH development. 27,28,50 The second mechanism involves targeting epithelial AR to influence BPH development via modulation of EMT to influence BPH development. 51 EMT, which is characterized by decrease of epithelial markers, including E-cadherin, and increase of mesenchymal (stromal) factors, including N-cadherin, vimentin, and Snail, 52 is a continual progression of epithelial cells to acquire the motile characteristics of mesenchymal cells.…”

Section: Stromal Ar Roles In Prostatementioning

confidence: 99%

Stromal Androgen Receptor Roles in the Development of Normal Prostate, Benign Prostate Hyperplasia, and Prostate Cancer

Wen

Chang

Tian

et al. 2015

The American Journal of Pathology

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The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.

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“…[12–14] SARMs have begun to be studied in the pre-clinical and clinical phases as treatment options for cancer related cachexia, breast cancer, benign prostatic hyperplasia, and hypogonadism. [2,15,16] There are several ongoing Phase 1 or Phase 2 clinical trials investigating the use of SARMs.…”

Section: Introductionmentioning

confidence: 99%

Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications

Solomon

Mirabal

Mazur

et al. 2019

Sexual Medicine Reviews

135

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Introduction: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM’s chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance enhancing agents. Here, we evaluate and summarize the current literature on SARMs. Aims: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs. Methods: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido and lean muscle mass. Both basic research and clinical studies were included. Results: While there are currently no FDA-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia, hypogonadism, and breast cancer, with positive results. Conclusion: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer.

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Anti‐androgenic effects of S‐40542, a novel non‐steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia

Abstract: The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists.

Cited by 21 publications

References 21 publications

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Stromal Androgen Receptor Roles in the Development of Normal Prostate, Benign Prostate Hyperplasia, and Prostate Cancer

Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications

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