Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis

Abstract

Estrogenic and inflammatory components play key roles in a broad range of diseases including endometriosis, a common estrogen-dependent gynecological disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, causing pelvic pain and reduced fertility. Current medical therapies focus primarily on reducing systemic levels of estrogens, but these are of limited effectiveness and have considerable side effects. We developed estrogen receptor (ER) ligands, chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which showed strong ER-dependent anti-inflammatory activity in a preclinical model of endometriosis that recapitulates the estrogen dependence and inflammatory responses of the disease in immunocompetent mice and in primary human endometriotic stromal cells in culture. Estrogen-dependent phenomena, including cell proliferation, cyst formation, vascularization, and lesion growth, were all arrested by CLI or OBHS, which prevented lesion expansion and also elicited regression of established lesions, suppressed inflammation, angiogenesis, and neurogenesis in the lesions, and interrupted crosstalk between lesion cells and infiltrating macrophages. Studies in ERα or ERβ knockout mice indicated that ERα is the major mediator of OBHS effectiveness and ERβ is dominant in CLI actions, implying involvement of both ERs in endometriosis. Neither ligand altered estrous cycling or fertility at doses that were effective for suppression of endometriosis. Hence, CLI and OBHS are able to restrain endometriosis by dual suppression of the estrogen-inflammatory axis. Our findings suggest that these compounds have the desired characteristics of preventive and therapeutic agents for clinical endometriosis and possibly other estrogen-driven and inflammation-promoted disorders.

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

“…Cleaved SRC-1 renders the ectopic endometrium resistant to the inflammatory and apoptotic signals elicited by TNF. In pre-clinical studies, compounds that selectively target ERα and ERβ effectively block lesion growth, angiogenesis, and neurogenesis associated with endometriosis (40). Recently, ERβ gain-of-function was shown to contribute to endometriotic lesion establishment and progression by evading the immune cell surveillance in mice (41).…”

The cytochrome P4501A1 gene polymorphisms and endometriosis: a meta-analysis

“…Moreover, CYP1A1 is also involved in estrogen metabolism, catalyzing the hydroxylation of 17β-estradiol at the C-2 position [31]. Considering that estrogenic components play key roles in endometriosis [32], CYP1A1 may be associated with endometriosis. The CYP1A1 MspI polymorphism can alter the level of gene expression or mRNA stability, resulting in a highly inducible activity of the enzyme [33].…”

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

“…Immunohistochemistry was performed on paraffin-embedded tissue sections as before (26). A mouse monoclonal anti-human ERα antibody (Novacastra, Cat# NCL-L-ER-6F11) was used at 1:300 dilution.…”