Benzopyrans Are Selective Estrogen Receptor β Agonists with Novel Activity in Models of Benign Prostatic Hyperplasia

Norman, Bryan H.; Dodge, Jeffrey A.; Richardson, Timothy I.; Borromeo, Peter S.; Lugar, Charles W.; Jones, Scott A.; Chen, Keyue; Wang, Yong; Durst, Gregory L.; Barr, R. J.; Montrose‐Rafizadeh, Chahrzad; Osborne, Harold E.; Amos, Robert M.; Guo, Sherry; Boodhoo, and Amechand; Krishnan, Venkatesh

doi:10.1021/jm060491j

Cited by 93 publications

(65 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the use of phyto-SERMs as effective therapeutic agents against BPH is limited by their weak activity. Nevertheless, the activity of phyto-SERMs can by potentiated quite appreciably by structural modifications of its ER-ß selective benzopyran moiety [20,21]. Designed synthesis of a series of potent benzopyran-SERMs was carried out at the Central Drug Research Institute [22][23][24], before the discovery of ER-ß, essentially for female contraception.…”

Section: Introductionmentioning

confidence: 99%

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

et al. 2010

View full text Add to dashboard Cite

The existing drugs for benign prostatic hyperplasia (BPH) are partially effective with undesirable side-effects; hence new agents acting by different mechanism(s) are required as supplements. Modulation of estrogen receptor signaling using selective estrogen receptor modulators (SERMs) offers an alternative approach for BPH management. Using human BPH-derived stromal cells and tissue explants in culture we evaluated two SERMs, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2 H-1-benzopyran (BP) and Ormeloxifene (Orm) in comparison to Tamoxifen (Tam) and 4-hydroxytamoxifen (OHT). BP, OHT and Tam were more effective than Orm in reducing stromal cell proliferation of human BPH. BP was either equipotent or more effective than OHT and Tam in increasing estrogen receptor(ER)-ß, TGFß1, Fas and FasL, and in decreasing ER-α, AR, EGF-R and IGF-I expressions in BPH stromal cells. BP, Tam and Orm (1.0 mg/Kg) reduced rat prostate weights by almost same extent as Finasteride (Fin, 5.0 mg/Kg); however combination treatment (SERM+Fin) was more effective. BP was exceptionally efficient in reducing IGF-1 and cleaving PARP while combination treatments more effectively increased bax:bcl-2 ratio. Fin reduced acinar diameter and prostatic DHT level but increased testosterone, estradiol (E(2)) and E(2)/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E(2)/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E(2), T and E(2)/T+DHT. The study reveals the potential of SERMs per se for BPH management, and more effectively in combination with a 5α-reductase inhibitor. BP appears promising for further evaluation as a drug candidate for BPH and prostate cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

et al. 2010

View full text Add to dashboard Cite

show abstract

“…While fulvestrant is an ER antagonist, attention has now turned towards developing ER agonists. Benzopyran-derived selective estrogen receptor beta-agonist-1 (SERBA-1) is a selective ER receptor agonist which has been studied in mice and prostate hyperplasia, with promising effects (Norman et al, 2006). Monoaryl-substituted salicylaldoximes also show high ER affinity and are interesting new compounds (Bertini et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Steroid Hormones and Ovarian Cancer

King¹,

Wong²

2011

Steroids - Clinical Aspect

View full text Add to dashboard Cite

“…The ERβ-selective agonist, DPN, however, prevented inflammation and the development of hyperplasia in the testosterone-treated LuRKO mice [471]. SERBA-1, a novel ERβ-selective agonist, was reported to have desired effects in a model of benign prostatic hyperplasia without feed-back effects on testosterone and dihydrotestosterone levels [472]. In many types of cancers, including prostate cancer, the expression of ERβ decreases over time due to epigenetic silencing [473][474][475][476].…”

Section: Prostate Cancermentioning

confidence: 99%

“…Ligands with ER subtype-selective affinity and biological activity have been reported [113,284,272,285,390,283,115,413,482,385,341,472,355,464,471,414,410,286,412,418,420,407,426,477]. A herbal extract with roughly similar affinity to both ERα and ERβ but with ERβ-selective transcriptional and biological activity has been described [439,446].…”

Section: Development Of Estrogen Receptor Subtype-selective Ligandsmentioning

confidence: 99%

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

Nilsson

Gustafsson²

2010

Nuclear Receptors

View full text Add to dashboard Cite

Abstract:Our view of estrogen signalling has undergone a paradigm shift over the recent 10-15 years with the discovery of a second estrogen receptor, ERβ, in 1995 and the finding that estrogens play an important role also in male physiology. Aromatase deficient patients and aromatase knock-out mice have highlighted the importance of estrogens in development and metabolic homeostasis while ER knock-out mice, ERα-/-and ERβ-/-, have shown that both ERs are of physiological importance and that ERα and ERβ have distinct and non-overlapping functions in the body. The uses of ER subtype-selective ligands in various animal models have further substantiated the distinctive physiological roles of ERα and ERβ and shown that they, in many contexts, are antagonistic against one another. Structural studies of the ligand-binding domains of ERα and ERβ have provided in-depth information on ligand recognition, receptor activation, and recruitment of coregulators. The cloning of coregulators and chromatin modulators together with sophisticated methodology to study gene regulation has significantly increased our understanding of cellular and target gene responses to estrogens, SERMs, and ER subtype-selective ligands. This book chapter will review our current understanding of the mechanisms of ERα-and ERβ-dependent estrogen signalling, the role of ERα and ERβ in health and disease, and the potential clinical uses of ERα-and ERβ-selective pharmaceuticals. INTRODUCTION AND HISTORICAL PERSPECTIVEIn the late nineteenth century two scientists made the observation that female sex steroid hormones played an essential role in promoting mammary tumour growth [1,2]. A little more than half a century later the pioneering endocrinologists, Jensen and Jacobsen [3,4], arrived at the conclusion that the biological effects of 17β-estradiol (E2) could be mediated through a specific receptor rather than through enzymatic metabolism of estradiol itself. A few years later the groups of Gorski and Jensen isolated and characterized an estrogen-binding protein from the uterus and proposed a model for its mechanism of action [5][6][7]. For many years this protein and 91

show abstract

Benzopyrans Are Selective Estrogen Receptor β Agonists with Novel Activity in Models of Benign Prostatic Hyperplasia

Cited by 93 publications

References 18 publications

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

Steroid Hormones and Ovarian Cancer

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

Contact Info

Product

Resources

About