title: NJK14013, a novel synthetic estrogen receptor-α agonist, exhibits estrogen receptor-independent, tumor cell-specific cytotoxicity.
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.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Hye-In
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Taelim
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Jinyuk
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics*; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; C416830:GREB1 protein, human; D009363:Neoplasm Proteins; D010091:Oximes; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C000605939:bis(4-hydroxyphenyl)methanone-O-isopentyl oxime