BIS-INDOLE DERIVED NUCLEAR RECEPTOR 4A1 (NR4A1, Nur77) LIGANDS AS INHIBITORS OF ENDOMETRIOSIS.

BIS-INDOLE DERIVED NUCLEAR RECEPTOR 4A1 (NR4A1, Nur77) LIGANDS AS INHIBITORS OF ENDOMETRIOSIS. Endocrinology. 2020 Feb 26;: Authors: Mohankumar K, Li X, Sung N, Cho YJ, Han SJ, Safe S Abstract Endometriosis is an inflammatory disease that primarily affects women during their reproductive years and since current hormonal therapies are of concern new hormone-independent treatment regimens are needed. The orphan nuclear receptor 4A1 (NR4A1, Nur77) is expressed in patient-derived (stromal) endometriotic cells and also epithelial cell lines, and we observed that knockdown of NR4A1 in patient-derived ESECT-7 and ESECT-40 cells decreased cell proliferation and induced apoptosis. Moreover, the treatment of these cells with bis-indole derived NR4A1 ligands 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and its buttressed 3-chloro-5-methoxy analog (DIM-C-pPhOH-3-Cl-5-OCH3) inhibited cell growth and induced apoptosis and related genes. The compounds exhibit NR4A1 antagonist activities in both functional and transactivation assays whereas these effects were not observed in normal (NEM) endometrial cells. We also observed that NR4A1 knockdown and treatment with NR4A1 antagonists decreased fibrosis, α-smooth muscle actin (α-SMA), and related pro-fibrotic genes in ESECT-7 and ESECT-40 cells, and similar results were observed in epithelial-derived endometriotic cell lines. Moreover, in an endometriosis mouse model with auto-transplan...
Source: Endocrinology - Category: Endocrinology Authors: Tags: Endocrinology Source Type: research