title: A novel compound, NK150460, exhibits selective antitumor activity against breast cancer cell lines through activation of aryl hydrocarbon receptor.
abstract: Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17β-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan. Department of Urology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan. kazuteru.fukasawa@nipponkayaku.co.jp.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Fukasawa
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Shigehide
authors.initials: S
authors.lastname: Kagaya
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kuroiwa
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kameyama
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akatsu
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Tomura
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Urology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horie
authors.affiliation: Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd., Kita-ku, Tokyo, Japan.
authors.forename: Yuh-ichiro
authors.initials: Y
authors.lastname: Ichikawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism; D008819:Mice, Nude; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011923:Rats, Nude; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: C000602443:7-methyl-3-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrocinnolin-5-ol; C497396:ARNT protein, human; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004967:Estrogens; D006574:Heterocyclic Compounds, 2-Ring; D011804:Quinolines; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019363:Cytochrome P-450 CYP1A1