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

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Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
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Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
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Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
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Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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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. View Full-Text
Keywords: aryl hydrocarbon receptor; raloxifene; Y134; estrogen receptor modulator; hepatoma; agonist; antagonist; anti-cancer drug; triple negative breast cancer; apoptosis 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. https://doi.org/10.3390/biology6040041

AMA Style

Jang HS, Pearce M, O’Donnell EF, Nguyen BD, Truong L, Mueller MJ, Bisson WH, Kerkvliet NI, Tanguay RL, Kolluri SK. Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells. Biology. 2017; 6(4):41. https://doi.org/10.3390/biology6040041

Chicago/Turabian Style

Jang, Hyo S.; Pearce, Martin; O’Donnell, Edmond F.; Nguyen, Bach D.; Truong, Lisa; Mueller, Monica J.; Bisson, William H.; Kerkvliet, Nancy I.; Tanguay, Robert L.; Kolluri, Siva K. 2017. "Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells" Biology 6, no. 4: 41. https://doi.org/10.3390/biology6040041

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