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-α, 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-α 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-α 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-α. 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.
Footnotes
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This work is supported by the National Institutes of Environmental Health Sciences Grant ES 008088. This work in part was presented at the 95th Annual Meeting of the American Association for Cancer Research, 2004 March 27–31; Orlando, FL; and the 43rd Annual Meeting of the Society of Toxicology, 2004 March 21–25; Baltimore, MD.
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doi:10.1124/jpet.105.084186.
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ABBREVIATIONS: AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; DRE, dioxin response element; NF-κB, nuclear factor κB; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, 2,3,7,8-tetrachlorodibenzo-p-furan; MNF, 3′-methoxy-4′-nitroflavone; DMSO, dimethyl sulfoxide; conDRE, consensus DRE; PCR, polymerase chain reaction; EMSA, electromobility shift assay; MOPS, 3-(N-morpholino)propanesulfonic acid.
- Received January 27, 2005.
- Accepted April 18, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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