The aryl hydrocarbon receptor in anticancer drug discovery: Friend or foe?

Binding of ligands such as polycyclic aromatic hydrocarbons to the Aryl hydrocarbon Receptor (AhR) and the sequence of events leading to induction of xenobiotic-metabolising enzymes such as the cytochrome P450 isoform 1A1 and subsequent generation of DNA adducts is historically associated with the process of chemical carcinogenesis. Cancer chemopreventative agents, on the other hand, often exert their biological effect at least in part through antagonism of AhR-induced carcinogenesis. A third scenario associated with AhR binding could occur if the induction of xenobiotic enzymes and subsequent DNA damage causes apoptosis. If this occurs selectively in tumour cells whilst sparing normal tissue, the AhR ligand would have a therapeutic cytotoxic effect. In this review we survey for the first time the major classes of reported AhR ligands and discuss the biological consequences of AhR binding in each case. The use of AhR ligands as cancer chemotherapeutic agents, as illustrated by the case of the 2-(4-aminophenyl)benzothiazole prodrug Phortress, is discussed as a therapeutic strategy.