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.

• Authors: Yuechao Zhao, Ping Gong, Yiru Chen, Jerome C Nwachukwu, Sathish Srinivasan, CheMyong Ko, Milan K Bagchi, Robert N Taylor, Kenneth S Korach, Kendall W Nettles, John A Katzenellenbogen, Benita S Katzenellenbogen
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 271 Pg. 271ra9 (Jan 21 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 25609169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Anti-Inflammatory Agents
• Estrogens
• Indazoles
• Ligands
• Nitriles
• Receptors, Estrogen
• Triazoles
• Letrozole

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cell Survival (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Disease Progression
• Drug Therapy, Combination
• Embryonic Stem Cells (drug effects, metabolism)
• Endometriosis (drug therapy, pathology, prevention & control)
• Estrogens (metabolism)
• Female
• Fertility (drug effects)
• Humans
• Indazoles
• Inflammation (pathology)
• Letrozole
• Ligands
• Macrophages (drug effects, pathology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (drug effects, pathology)
• Nitriles (pharmacology, therapeutic use)
• Receptors, Estrogen (metabolism)
• Stromal Cells (drug effects)
• Treatment Outcome
• Triazoles (pharmacology, therapeutic use)