Targeting key dioxygenases in tryptophan–kynurenine metabolism for immunomodulation and cancer chemotherapy

Austin, Christopher; Rendina, Louis M.

doi:10.1016/j.drudis.2014.11.007

Cited by 75 publications

(69 citation statements)

References 70 publications

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“…1MLT preferentially inhibits IDO1 (Opitz et al , 2011; Austin and Rendina, 2015) and 1MDT appears to inhibit TDO2, IDO1, and IDO2 to varying degrees (Metz et al , 2007; Löb et al , 2009; Austin and Rendina, 2015). 1MLT is a test compound in several clinical trials (Rohrig et al , 2015) (Table 1), and like the other tested IDO1 inhibitors, plasma concentrations in the course of treatment in clinical trials reaches the micromolar range (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The essential amino acid L-Tryptophan (Trp) is metabolized in a tissue-specific manner by the rate-limiting enzymes tryptophan 2,3-dioxygenase 2 (TDO2) and indoleamine 2,3-dioxygenase (IDO1 and IDO2) to produce L-Kynurenine (Kyn) (Austin and Rendina, 2015). IDO1 has garnered the most attention due to its key roles in inflammation, as Trp metabolites, particularly Kyn, act as regulators of immune cell differentiation and proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, IDO1 is a popular target for chemotherapeutic intervention, with a number of IDO1 inhibitors currently being tested in cancer clinical trials (Vacchelli et al , 2014; Austin and Rendina, 2015; Rohrig et al , 2015). For example, INCB024360 (INCB) is involved in at least eight clinical trials, either as a single agent or in combination with other drugs for treatment of melanomas, reproductive tract cancers, and other solid tumors; while NLG919 (NLG) is in a phase I clinical trial for treatment of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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

Moyer

Rojas

Murray

et al. 2017

Toxicology and Applied Pharmacology

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SUMMARY 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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Moyer

Rojas

Murray

et al. 2017

Toxicology and Applied Pharmacology

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show abstract

“…Nevertheless it appears that a global tryptophan to kynurenine metabolism inhibitor able to block both TDO, IDO1 and IDO2 could improve efficacy in cancer treatment. Interestingly a series of classical antifungal imidazoles such as econazole, clotrimazole displayed such a global inhibitory activity that could be used in clinic has they showed little effect on cellular toxicity [89].…”

Section: Tryptophan Metabolism and Cancermentioning

confidence: 99%

Is tryptophan metabolism involved in sleep apnea-related cardiovascular co-morbidities and cancer progression?

et al. 2015

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“…Overall, IDO-induced Trp depletion triggers an immunosuppressive environment via depletion, anergy, and apoptosis of T-cells. Thus, IDO-induction plays an important role in the development of immunological tolerance and IDO-induced immunosuppression is used by solid malignancies to protect themselves from immune recognition and cytotoxicity - a fact that is recognized as a key tumour escape mechanism [9,10,13,14,15,16,17,18,19,20]. …”

Section: Introductionmentioning

confidence: 99%

Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia

Pschowski

Pape²,

Fusch³

et al. 2016

Neuroendocrinology

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Background/Aims: Data from a considerable number of malignancies demonstrate that depletion of the essential amino acid tryptophan via induction of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO) serves as an important tumour escape strategy and is of prognostic importance. Here we investigate the predictive value of the activity of IDO as well as levels of tryptophan and respective downstream catabolites in a large cohort of patients with neuroendocrine neoplasms (NEN). Methods: 142 consecutive Caucasian patients (62 male, aged 60.3 ± 11.9 years) with histologically confirmed NEN were systematically analysed in a retrospective blinded end point analysis. Patients were followed up for a mean period of about 3.9 ± 1.9 years. Clinical outcome, levels of established biomarkers, and tryptophan degradation markers (assessed using tandem mass spectrometry) including estimated IDO activity were recorded. Cox proportional hazards regression models were performed for the assessment of prognostic power. Results: We found that baseline tryptophan levels were significantly lower and IDO activity was significantly increased in non-survivors. The risk for death inclined stepwise and was highest in patients in the upper tertile of IDO activity. Cox proportional regression models identified IDO activity as an independent predictor of death. Conclusions: In this retrospective analysis, we observed that baseline activity of the immunoregulatory enzyme IDO was significantly increased in non-survivors. IDO activity was identified as an independent predictor of death in this cohort of NEN patients. Whether IDO activity or tryptophan depletion serves to guide future therapeutic interventions in NEN remains to be established.

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Targeting key dioxygenases in tryptophan–kynurenine metabolism for immunomodulation and cancer chemotherapy

Cited by 75 publications

References 70 publications

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

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

Is tryptophan metabolism involved in sleep apnea-related cardiovascular co-morbidities and cancer progression?

Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia

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