Pifithrin-α, an experimental inhibitor of cancer therapy toxicity, is a potent aryl hydrocarbon receptor agonist.

2029

Pifithrin-α (PFTa) is a chemical compound that inhibits p53-dependent apoptosis through an undetermined mechanism. Since the toxicities of most chemotherapeutic agents are most frequently associated with p53 activation and apoptosis in healthy cells, PFTa is currently being evaluated in pre-clinical trials for its ability to alleviate these side effects. Given the structural similarities between PFTa and AhR (aryl hydrocarbon receptor) agonists, we hypothesized that PFTa may act as an AhR ligand. Activation of AhR results in translocation to the nucleus, dimerization to its DNA-binding partner (ARNT), and regulation of gene transcription through binding of DNA at dioxin-response elements (DREs). A well-characterized effect of AhR ligands β-naphthoflavone (BNF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the up-regulation of xenobiotic-metabolizing enzymes including CYP1A1, CYP1A2, and CYP1B1. In this study, we have characterized PFTa as a potent AhR agonist by demonstrating that PFTa is able to 1) activate gene expression through the CYP1A1 gene promoter as well as DREs, 2) induce expression of CYP1A1, 3) induce DNA binding by AhR/ARNT, as well as 4) competitively displace [³H]TCDD from AhR. These studies imply that the ability of PFTa to inhibit p53-mediated apoptosis may require its activation of the AhR signaling pathway.