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• W2045280145 startingPage "603" @default.
• W2045280145 abstract "The tumor suppressor protein p53 is currently a target of emerging drug therapies directed toward neurodegenerative diseases, such as Alzheimer's and Parkinson's, and side effects associated with cancer treatments. Of this group of drugs, the best characterized is pifithrin-alpha, a small molecule that inhibits p53-dependent apoptosis through an undetermined mechanism. In this study, we have used a number of molecular approaches to test the hypothesis that pifithrin-alpha acts as an aryl hydrocarbon receptor (AhR) agonist and, in this manner, inhibits the actions of p53. Toward this end, we have found that pifithrin-alpha is a potent AhR agonist as determined by its ability to bind the AhR, induce formation of its DNA binding complex, activate reporter activity, and up-regulate the classic AhR target gene CYP1A1. However, examination of its ability to inhibit p53-mediated gene activation and apoptosis revealed that these actions occurred via an AhR-independent manner. The significance of this study is based on the fact that activation of the AhR is typically associated with an increase in phase I and phase II metabolizing enzymes and adverse biological events such as tumor promotion that may contribute to untoward effects of pifithrin-alpha. Hence, this work will aid in the future design of more specific members of this important class of p53 inhibitors for use in a clinical setting." @default.
• W2045280145 created "2016-06-24" @default.
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• W2045280145 date "2005-04-20" @default.
• W2045280145 modified "2023-09-27" @default.
• W2045280145 title "The p53 Inhibitor Pifithrin-α Is a Potent Agonist of the Aryl Hydrocarbon Receptor" @default.
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• W2045280145 doi "https://doi.org/10.1124/jpet.105.084186" @default.
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