title: 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.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yuechao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.affiliation: Department of Cancer Biology, Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: CheMyong
authors.initials: C
authors.lastname: Ko
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.affiliation: Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
authors.affiliation: Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: Department of Cancer Biology, Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. katzenel@illinois.edu.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000187:drug effects; D006801:Humans; D007191:Indazoles; D007249:Inflammation / Q000473:pathology*; D000077289:Letrozole; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D004967:Estrogens; D007191:Indazoles; D008024:Ligands; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole