Graduate Thesis Or Dissertation

 

Discovery and mechanism of action of anti-cancer compounds targeting the aryl hydrocarbon receptor Public Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/gx41mp446

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  • The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor belonging the basic helix-loop-helix Per/Arnt/Sim (bHLH PAS) family of proteins. The AhR has long been studied for its role in mediating the effects of environmental toxicants, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). By studying the mechanism of action of TCDD, the AhR has been shown to be involved in numerous biological functions and processes, including metabolism of xenobiotics, the adaptive immune response, embryonic development, and cell cycle regulation. The AhR has also been shown to act as a tumor suppressor gene in several mouse models of cancer. In addition, the AhR is highly expressed in a number of different cancers. We hypothesized that structurally diverse ligands of the AhR have different effects on AhR function, and that it is possible to activate anti-cancer properties of the AhR without inducing dioxin-like toxicity. To this end, we screened a small molecule library of pharmacologically active compounds including FDA-approved drugs, with the specific intent of repurposing such drugs as AhR-based anti- cancer therapeutics. We used a parallel screening approach, with one assay utilizing a xenobiotic response element (XRE) based reporter assay to identify traditional ligands of the AhR, and a second system consisting of a novel heterologous AhR-dependent reporter assay designed to identify novel AhR ligands distinct from those that activate XRE-driven genes. Using these approaches, and evaluating the phenotypic effects of putative hits in target cancer cell types, four lead compounds were selected for further evaluation, two of which are currently in use in clinic: leflunomide, used to treatment rheumatoid arthritis, and raloxifene, a selective estrogen receptor (ER) modulator used to prevent osteoporosis and ER-positive breast cancer. The mechanisms of action of the lead compounds were characterized in terms of AhR activation and AhR- dependent anti-cancer effects. We showed that leflunomide inhibits growth of melanoma cells in an AhR-dependent manner through a mechanism distinct from its current use in the clinic. Two of the lead compounds were found to induce AhR-dependent apoptosis, with raloxifene exhibiting anti-cancer effects in hormone-independent breast cancer cells. The AhR ligands characterized in this work, including leflunomide and raloxifene, represent a novel small molecule probe set that can be used to better characterize the anti-cancer properties of the AhR. The AhR-dependent phenotypes of these compounds compared to AhR ligands such as TCDD will also be useful for establishing a molecular basis for how the AhR facilitates diverse biological outcomes in response to activation by distinct ligands. Development of these compounds, especially raloxifene, as AhR-targeted anti- cancer therapeutics will be useful for establishing the AhR as a viable anti-cancer target.
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  • description.provenance : Approved for entry into archive by Laura Wilson(laura.wilson@oregonstate.edu) on 2013-05-29T21:52:58Z (GMT) No. of bitstreams: 1ODonnellEdmondF2013.pdf: 110543895 bytes, checksum: b6a03a52a84f7363b18b68cb131825eb (MD5)
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  • 2017-11-06 to 2018-05-22

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