TitleIdentification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells
Publication TypeJournal Article
Year of Publication2017
AuthorsJang, H, Pearce, MC, O'Donnell, EF, Nguyen, B, Truong, L, Mueller, MJ, Bisson, WH, Kerkvliet, NI, Tanguay, RL, Kolluri, S
JournalBiology (Basel)
Volume6
Issue4
Date Published2017
Keywordsagonist, antagonist, anti-cancer drug, Apoptosis, Aryl hydrocarbon receptor, estrogen receptor modulator, hepatoma, raloxifene, triple negative breast cancer, Y134
Abstract

We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis. We identified Y134 as a raloxifene analog that activates AhR-mediated transcriptional activity and induces apoptosis in MDA-MB-231 human triple negative breast cancer cells. Suppression of AhR expression strongly reduced apoptosis induced by Y134, indicating the requirement of AhR for Y134-induced apoptosis. Y134 also induced apoptosis in hepatoma cells without having an effect on cell cycle regulation. Toxicity testing on zebrafish embryos revealed that Y134 has a significantly better safety profile than raloxifene. Our studies also identified an analog of raloxifene that acts as a partial antagonist of the AhR, and is capable of inhibiting AhR agonist-induced transcriptional activity. We conclude that Y134 is a promising raloxifene analog for further optimization as an anti-cancer agent targeting the AhR.