Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells

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

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.