Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells
by
Hyo Sang Jang 1, Martin Pearce 1, Edmond F. O’Donnell 1,†, Bach Duc Nguyen 1, Lisa Truong 2
, Monica J. Mueller 1, William H. Bisson 3, Nancy I. Kerkvliet 2, Robert L. Tanguay 2,4,5 and Siva Kumar Kolluri 1,2,4,5,*
Hyo Sang Jang 1, Martin Pearce 1, Edmond F. O’Donnell 1,†, Bach Duc Nguyen 1, Lisa Truong 2, Monica J. Mueller 1, William H. Bisson 3, Nancy I. Kerkvliet 2, Robert L. Tanguay 2,4,5 and Siva Kumar Kolluri 1,2,4,5,*
1
Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
2
Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
3
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
4
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
5
Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331, USA
*
Author to whom correspondence should be addressed.
†
Current address: Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.
Academic Editor: Jukka Finne
Biology 2017, 6(4), 41; https://doi.org/10.3390/biology6040041
Received: 30 September 2017 / Revised: 14 November 2017 / Accepted: 22 November 2017 / Published: 1 December 2017
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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Keywords:
aryl hydrocarbon receptor; raloxifene; Y134; estrogen receptor modulator; hepatoma; agonist; antagonist; anti-cancer drug; triple negative breast cancer; apoptosis
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MDPI and ACS Style
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. Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells. Biology 2017, 6, 41.
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