Effect of Indirubin, Indole-3-carbinol and β-Naphthoflavone on the Aryl Hydrocarbon Receptor/Cytochrome 450 Signaling Pathway in Various Human Cell Lines

Indirubin, indol-3-carbinol and beta-naphthoflavone have been proposed as potential agents for treating a variety of cancers. These compounds are well characterized AHR ligands. AHR is a ligand-dependent cytosolic transcription factor that induces the transcription of target genes, such as the cytochromes P450 (CYP). The CYP enzymes are involved in the metabolic activation of anticancer drugs, hinting at their potential involvement in both the development and treatment of cancer. Our research focused on the AHR/CYP1 signaling pathway in human cell lines (HEK293, PC3, Mcf7, Sus/fP2), examining its effects induced by ligands. We assessed how these substances affected the expression of CYP1 genes and explored the correlation between these responses and changes in AHR protein levels in human cell lines. The findings reveal that the AHR/CYP1 signaling pathway remains functional in PC3 and Sus/fP2. In HEK293 cells, the AHR protein levels exhibited no change following to each ligand and the CYP1 gene expression was downregulated. However, in Mcf7 cells, a high level of CYP1 responsiveness was observed along with unchanged AHR protein levels after exposure to ligands that correlated with ER alpha expression levels. These findings underscore the importance of considering the AHR/CYP1 signaling pathway when developing new strategies for cancer treatment.