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.

The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

“…Similar results were observed for head and neck cancer where AhR antagonists were effective as anticancer agents [49]. The growth and invasion of breast and other cancers are inhibited by AhR agonists, and there has been development of relatively non-toxic SAhRMs which include aminoflavone and NKI150460, a novel selective anticancer agent and AhR agonist, for treatment of breast cancer [14,50]. Among the more classical AhR ligands, indole-3-carbinol (from cruciferous vegetables) and β-naphthoflavone and its dimer, diindolylmethane (DIM), exhibit promising anticancer activity and these compounds and synthetic analogs should be further investigated for their potential clinical applications.…”

The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer

“…Added to the fact that the structure of curcumin represents myriad avenues for structural modification and pharmacological manipulation, enhancing its AHR targeting may one day produce novel chemopreventives and anticancer agents for colorectal cancer (21, 54). In fact, small molecule agonists of the AHR are already under investigation to combat cancer in other tissues (55). …”

Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells

“…Recent paradigm of promising anti-breast cancer candidates has revealed that Ahr mediates their therapeutic potential. For example, (5S,7S)-7-methyl-3-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrocinnolin-5-ol (NK150460) suppresses growth of different estrogen receptor (ER)-negative and ER-positive breast cancer cell lines via the molecular cascade of Ahr/Arnt [11]. The Ahr mediates the inhibitory effects of 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109) on growth and invasion of MDA-MB-231 through upregulation of Hsp70-interacting protein (CHIP) [12].…”