2. Academic Validation
  3. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor

  • Toxicol Appl Pharmacol. 2017 May 15;323:74-80. doi: 10.1016/j.taap.2017.03.012.
Benjamin J Moyer 1,  Itzel Y Rojas 2,  Iain A Murray 3,  Seokwon Lee 2,  Haley F Hazlett 2,  Gary H Perdew 3,  Craig R Tomlinson 4
Affiliations

Affiliations

  • 1 Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
  • 2 Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
  • 3 Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, United States; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, United States.
  • 4 Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States. Electronic address: Craig.R.Tomlinson@Dartmouth.edu.
PMID: 28336214 DOI: 10.1016/j.taap.2017.03.012
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for Cancer treatment as well as several Other Diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 Enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the Aryl Hydrocarbon Receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes.

Keywords

AHR agonists; Aryl Hydrocarbon Receptor; Cancer; Clinical trials; IDO inhibitors; IDO1.

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