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

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. - Highlights: • Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors are in cancer clinical trials. • Some IDO1 inhibitors also potently activate AHR signaling. • The dualmore » role of the IDO1 inhibitors may explain some past paradoxical findings. • AHR induction studies must be included in assessing clinical suitability.« less

Authors:
 [1];  [2];  [3]; ;  [2];  [3]
  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)
Publication Date:
OSTI Identifier:
22690979
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 323; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BEARS; CELL DIFFERENTIATION; CLINICAL TRIALS; DIOXIN; DMSO; DRUGS; ENZYME ACTIVITY; GENES; HYDROXY COMPOUNDS; KYNURENINE; LIGANDS; LUCIFERASE; MEDICAL SURVEILLANCE; METABOLISM; MICE; NEOPLASMS; PHOSPHATES; QUINOLINES; RECEPTORS; SUBSTRATES; TRYPTOPHAN; XENOBIOTICS

Citation Formats

Moyer, Benjamin J., Rojas, Itzel Y., Murray, Iain A., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Lee, Seokwon, Hazlett, Haley F., Perdew, Gary H., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Tomlinson, Craig R., E-mail: Craig.R.Tomlinson@Dartmouth.edu, and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.03.012.
Moyer, Benjamin J., Rojas, Itzel Y., Murray, Iain A., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Lee, Seokwon, Hazlett, Haley F., Perdew, Gary H., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Tomlinson, Craig R., E-mail: Craig.R.Tomlinson@Dartmouth.edu, & Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. United States. doi:10.1016/J.TAAP.2017.03.012.
Moyer, Benjamin J., Rojas, Itzel Y., Murray, Iain A., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Lee, Seokwon, Hazlett, Haley F., Perdew, Gary H., Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, Tomlinson, Craig R., E-mail: Craig.R.Tomlinson@Dartmouth.edu, and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. Mon . "Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor". United States. doi:10.1016/J.TAAP.2017.03.012.
@article{osti_22690979,
title = {Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor},
author = {Moyer, Benjamin J. and Rojas, Itzel Y. and Murray, Iain A. and Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802 and Lee, Seokwon and Hazlett, Haley F. and Perdew, Gary H. and Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802 and Tomlinson, Craig R., E-mail: Craig.R.Tomlinson@Dartmouth.edu and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756},
abstractNote = {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. - Highlights: • Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors are in cancer clinical trials. • Some IDO1 inhibitors also potently activate AHR signaling. • The dual role of the IDO1 inhibitors may explain some past paradoxical findings. • AHR induction studies must be included in assessing clinical suitability.},
doi = {10.1016/J.TAAP.2017.03.012},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 323,
place = {United States},
year = {2017},
month = {5}
}