Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

Platten, Michael; Nollen, Ellen A. A.; Röhrig, Ute F.; Fallarino, Francesca; Opitz, Christiane A.

doi:10.1038/s41573-019-0016-5

Cited by 874 publications

(749 citation statements)

References 288 publications

(351 reference statements)

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“…The metabolism of tryptophan might be the most complicated one among AAs, and was involved in the regulation of immunity, neuronal function and intestinal homeostasis [44]. Majority (~95%) of absorbed tryptophan degraded via kynurenine pathway, in which IDOs and tryptophan-2,3-dioxygenase (TDO) were the main rate-limiting enzymes.…”

Section: Tryptophan Is the Least Used And Available Eaamentioning

confidence: 99%

“…Besides the usage for protein synthesis, a small fraction of tryptophan was catabolized by tryptophan hydroxylase (TPH) for the production of serotonin (5-hydroxytryptophan, 5-HT) and melatonin. Tryptophan and its metabolites were used and catabolized by various organs and cells to further generate bioactive metabolites, including neuroprotective kynurenic acid by astrocytes, neurotoxic quinolinic acid by microglia, neuromodulator tryptamine, immune suppressive metabolites (such as 3hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) [42,44]. The catabolism of tryptophan induced by IFN-γ in cancer cells and macrophages showed that the catabolites of tryptophan differed in kynurenine, anthranilic acid and 3-hydroxyanthranilic acid [40].…”

Section: Tryptophan Is the Least Used And Available Eaamentioning

confidence: 99%

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Dietary restriction of amino acids for Cancer therapy

Kang

2020

Nutr Metab (Lond)

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Biosyntheses of proteins, nucleotides and fatty acids, are essential for the malignant proliferation and survival of cancer cells. Cumulating research findings show that amino acid restrictions are potential strategies for cancer interventions. Meanwhile, dietary strategies are popular among cancer patients. However, there is still lacking solid rationale to clarify what is the best strategy, why and how it is. Here, integrated analyses and comprehensive summaries for the abundances, signalling and functions of amino acids in proteomes, metabolism, immunity and food compositions, suggest that, intermittent dietary lysine restriction with normal maize as an intermittent staple food for days or weeks, might have the value and potential for cancer prevention or therapy. Moreover, dietary supplements were also discussed for cancer cachexia including dietary immunomodulatory.

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Section: Tryptophan Is the Least Used And Available Eaamentioning

confidence: 99%

Section: Tryptophan Is the Least Used And Available Eaamentioning

confidence: 99%

Dietary restriction of amino acids for Cancer therapy

Kang

2020

Nutr Metab (Lond)

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“…In fact, enhanced Trp breakdown, reflected by decreased Trp and elevated kynurenine (Kyn) concentrations in the peripheral blood, is often observed in cancer patients and related to tumor progression, poor clinical outcome ( Table 1) and an impaired quality of life (QoL) (58,85). Trp breakdown in patients with malignancies is primarily mediated by increased tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 (IDO1) activities (86). The latter is primarily activated by proinflammatory cytokines of the T helper 1 (Th1) type immune response, particularly interferon gamma (IFN-γ) (87).…”

Section: Introductionmentioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

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“…Reciprocal interactions between metabolic pathways and immunity coordinate cross-talk between whole-body and immune cell functions and is involved in a variety of health and disease states (39). Among these pathways, metabolism of L-Tryptophan (Trp), one of the nine essential amino acid that is obtained exclusively from dietary intake in humans, regulates immune responses at multiple levels (40).…”

Section: Ido1 In Immune Regulationmentioning

confidence: 99%

“…Altogether these data suggest that IDO1 induction can control the host immune response and promote tolerance induction in several different contexts. Accordingly, dysregulation of Trp metabolism have been reported in various diseases including tumors, autoimmunity, and neurodegenerative diseases (40). Specifically, in different in vivo models, IDO1 expression has shown to have a protective effect on autoimmune encephalitis and pancreatic islet allograft (64,68).…”

Section: Ido1 In Immune Regulationmentioning

confidence: 99%

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1

et al. 2020

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The occurrence of neutralizing anti-FVIII antibodies is a major complication in the treatment of patients affected by hemophilia A. The immune response to FVIII is a complex, multi-factorial process that has been extensively studied for the past two decades. The reasons why only a proportion of hemophilic patients treated with FVIII concentrates develop a clinically significant immune response is incompletely understood. The "danger theory" has been proposed as a possible explanation to interpret the findings of some observational clinical studies highlighting the possible detrimental impact of inflammatory stimuli at the time of replacement therapy on inhibitor development. The host immune system is often challenged to react to FVIII under steady state or inflammatory conditions (e.g., bleeding, infections) although fine tuning of mechanisms of immune tolerance can control this reactivity and promote longterm unresponsiveness to the therapeutically administered factor. Recent studies have provided evidence that multiple interactions involving central and peripheral mechanisms of tolerance are integrated by the host immune system with the environmental conditions at the time of FVIII exposure and influence the balance between immunity and tolerance to FVIII. Here we review evidences showing the involvement of two key immunoregulatory oxygenase enzymes (IDO1, HO-1) that have been studied in hemophilia patients and pre-clinical models, showing that the ability of the host immune system to induce such regulatory proteins under inflammatory conditions can play important roles in the balance between immunity and tolerance to exogenous FVIII.

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Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

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Cited by 874 publications

References 288 publications

Dietary restriction of amino acids for Cancer therapy

Dietary restriction of amino acids for Cancer therapy

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1

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