PUBLICATION
Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells
- Authors
- Jang, H.S., Pearce, M., O'Donnell, E.F., Nguyen, B.D., Truong, L., Mueller, M.J., Bisson, W.H., Kerkvliet, N.I., Tanguay, R.L., Kolluri, S.K.
- ID
- ZDB-PUB-171204-40
- Date
- 2017
- Source
- Biology 6(4): (Journal)
- Registered Authors
- Tanguay, Robyn L.
- Keywords
- Y134, agonist, antagonist, anti-cancer drug, apoptosis, aryl hydrocarbon receptor, estrogen receptor modulator, hepatoma, raloxifene, triple negative breast cancer
- MeSH Terms
- none
- PubMed
- 29194351 Full text @ Biology (Basel)
Citation
Jang, H.S., Pearce, M., O'Donnell, E.F., Nguyen, B.D., Truong, L., Mueller, M.J., Bisson, W.H., Kerkvliet, N.I., Tanguay, R.L., Kolluri, S.K. (2017) Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells. Biology. 6(4).
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.
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