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- Title
Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells.
- Authors
Hyo Sang Jang; Pearce, Martin; O'Donnell, Edmond F.; Bach Duc Nguyen; Lisa Truong; Mueller, Monica J.; Bisson, William H.; Kerkvliet, Nancy I.; Tanguay, Robert L.; Kolluri, Siva Kumar
- 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.
- Subjects
RALOXIFENE; CANCER cells; ESTROGEN receptors
- Publication
Biology (2079-7737), 2017, Vol 6, Issue 4, p41
- ISSN
2079-7737
- Publication type
Article
- DOI
10.3390/biology6040041