RESUMEN
Natural products are widely used in different aspects of our lives - from household cleaners and food production, via cosmetics and aromatherapy, to both alternative and traditional medicine. In our research group, we have recently described several monoterpenoids with potential in the antiviral and anticancer therapy by allosteric targeting of aryl hydrocarbon receptor (AhR). Prior to any practical application, biological effects on human organism must be taken in concern. This review article is focused on the biological effects of 5 monoterpenoids on the human health previously identified as AhR antagonists with a therapeutic potential as antiviral and anticancer agents. We have thoroughly described cytotoxic, anti-inflammatory, anti-proliferative, and anticancer effects, as well as known interactions with nuclear receptors. As clearly demonstrated, monoterpenoids in general represent almost an inexhaustible reservoir of natural compounds possessing the ability to influence, modulate and improve human health.
RESUMEN
The human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding. Carvones do not displace radiolabeled ligands from binding to AhR but instead bind allosterically within the bHLH/PAS-A region of AhR. Carvones do not influence the translocation of ligand-activated AhR into the nucleus but inhibit the heterodimerization of AhR with its canonical partner ARNT and subsequent binding of AhR to the promoter of CYP1A1. As a proof of concept, we demonstrate physiologically relevant Ahr-antagonism by carvones in vivo in female mice. These substances establish the molecular basis for selective targeting of AhR regardless of the type of ligand(s) present and provide opportunities for the treatment of disease processes modified by AhR.