The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

Abstract

The aryl hydrocarbon receptor (AhR) is overexpressed in some patients with different tumor types, and the receptor can be a negative or positive prognostic factor. There is also evidence from both in vivo and in vitro cell culture models that the AhR can exhibit tumor-specific pro-oncogenic and tumor suppressor-like functions and therefore can be treated with AhR antagonists or agonists, respectively. Successful clinical applications of AhR ligands will require the synthesis and development of selective AhR modulators (SAhRMs) with tumor-specific AhR agonist or antagonist activity, and some currently available compounds such as indole-3-carbinol and diindolylmethane-(DIM) and synthetic AhR antagonists are potential drug candidates. There is also evidence that some AhR-active pharmaceuticals, including tranilast, flutamide, hydroxytamoxifen and omeprazole or their derivatives, may be effective AhR-dependent anticancer agents for single or combination cancer chemotherapies for treatment of breast and pancreatic cancers.

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

“…Recent evidence of DIM derivatives as chemopreventive agents against triple negative breast cancer hold promise from early demonstration studies of in vitro models[51]. Tumor-specific responses have also been described including aryl hydrocarbon receptor (AhR) agonistic activity [52] and sensitizing activity against gamma radiation [53]. These alternate pathways for chemopreventive activity are under active study and could be further explored using stored biosamples from the current trial.…”

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…The aryl hydrocarbon receptor (AhR) is a member of the basic helix‐loop‐helix/Per‐ARNT‐SIM (bHLH/PAS) transcription factor family, and it has been previously suggested that it is a possible druggable target . It is ligand activated by a variety of synthetic and natural compounds .…”

Expression of the IDO1/TDO2-AhR pathway in tumor cells or the tumor microenvironment is associated with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma

“…IDO is activated in tumor, stromal, and innate immune cells in various cancers, and its expression is correlated with a less favorable prognosis [20]. Increased TDO2 expression is associated with a higher grade, estrogen receptor-negative status, and a shorter overall survival (OS) in triple-negative breast cancer [21], whereas AhR overexpression in several cancers can be a positive or negative prognostic factor, depending on the type of cancer [22]. High AhR expression in breast cancer correlates with higher expression of several genes in inflammation, endogenous Trp metabolism, and the invasion signaling pathway [23].…”