NJK14013, a novel synthetic estrogen receptor-α agonist, exhibits estrogen receptor-independent, tumor cell-specific cytotoxicity

Abstract

Abstract. Estrogens act through interactions with estrogen receptors (ERs) to play diverse roles in various pathophysiological conditions. A number of synthetic selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been developed and used to treat ER-related diseases, including breast cancer and osteoporosis. Here, we identified a novel compound, bis(4-hydroxyphenyl) methanone-O-isopentyl oxime, designated NJK14013, as an ER agonist. NJK14013 activated ER-dependent transcription in a concentration-dependent manner, while suppressing androgen receptor-dependent transcriptional activity. It induced the activation-related phosphorylation of ER and enhanced the transcription of growth regulation by estrogen in breast cancer 1 (GREB1), further supporting its ER-stimulating activity. NJK14013 exerted anti-proliferative effects on various cancer cell lines, including an ER-negative breast cancer cell line, suggesting that it is capable of suppressing the growth of cancer cells independent of its ER-modulating activity. In addition, NJK14013 treatment resulted in significant apoptotic death of MCF7 and Ishikawa cancer cells, but did not induce apoptosis in non-cancer human umbilical vein endothelial cells. Collectively, our findings demonstrate that NJK14013 is a novel SERM that can activate ER-mediated transcription in MCF7 cells and suppress the proliferation of various cancer cells, including breast cancer cells and endometrial cancer cells. These results suggest that NJK14013 has potential as a novel SERM for anticancer or hormone-replacement therapy with reduced risk of carcinogenesis.

Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

“…Kaur and coworkers decribed Ospemifene analogues with stronger binding affinities with both ERα and ERβ compared to Ospemifene and Tamoxifen, exerting also cytotoxic effect on estrogen independent MDA-MB-231 cells [ 42 ]. On the other hand the novel entrogen receptor agonist inducing apoptotic death in various cancer cell types was described by Kim and coworkers [ 43 ].…”

Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors

“…The 4-hydroxyl group of the A-phenyl ring and the B-phenyl ring of BPA derivatives are essential for ERα-related transcriptional activity, with the bridging alkyl groups changing their respectively influences 42 . Bisphenol moieties connected by oxime esters show agonistic activity for ERα with suppress cell proliferation in cancer cells 43,44 . The estrogenic activities of contaminants in BPA used for industrial purposes were previously analysed by yeast two-hybrid assays 45 , identifying 4,4′-(1,3-dimethylbuthylidene)bisphenol as exerting 8-fold higher estrogenic activity than laboratory grade BPA.…”

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

“…Among them, bis(4-hydroxy)benzophenone oxime ether derivatives, including 229 (IC 50 75 nM), 230 (IC 50 46 nM), and 231 (IC 50 77 nM), were shown to possess estrogen receptor (ER) agonist properties associated with noticeable antiproliferative activities arising through an ER-independent mechanism in cancer cells [216]. Furthermore, compound 231 and its analog 232 were shown to upregulate the activity of an estrogen response element (ERE)-containing luciferase reporter construct (ERE-luciferase) in MCF7 cells [217]. Notably, 231 showed higher activity than E2, the endogenous ligand, at concentrations of 1000 nM and 100 nM, but exhibited only a marginal activity at 10 nM [217].…”