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1
Oweira, Hani, Imad Lahdou, Stefan Mehrle, Elias Khajeh, Rajan Nikbakhsh, Omid Ghamarnejad, Peter Terness, Christoph Reißfelder, Mahmoud Sadeghi, and Ali Ramouz. "Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepG2 Tumor Cells." Journal of Clinical Medicine 11, no. 16 (August 16, 2022): 4794. http://dx.doi.org/10.3390/jcm11164794.
Анотація:
There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.
2
Terai, Londin, Rochani, Link, Lam, Kaushal, Bhushan, Orloff, and Sato. "Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma." Cancers 12, no. 2 (February 10, 2020): 405. http://dx.doi.org/10.3390/cancers12020405.
Анотація:
Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM.
3
Kim, Chan, Joo Hoon Kim, Jin Sung Kim, Hong Jae Chon, and Joo-Hang Kim. "A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14228-e14228. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14228.
Анотація:
e14228 Background: Kynurenine production by indoleamine 2,3-dioxygenase (IDO) is critical for tumor immune suppression through effector T cell anergy and regulatory T cell proliferation. This has led to the rapid development of IDO inhibitors for cancer immunotherapy. However, results from recent clinical trials have been disappointing and this is partly due to pathway redundancy. Tryptophan 2,3-dioxygenase (TDO), another important enzyme of the kynurenine pathway, plays a compensatory role in the absence of IDO activity. Therefore, we developed a dual inhibitor of IDO and TDO to achieve maximal inhibition of the kynurenine pathway and alleviate tumor immune suppression. Methods: Small-molecule inhibitors of IDO and TDO were synthesized and evaluated using in vitro cell-based assays. Pharmacokinetic and pharmacodynamic profiles were assessed for these inhibitors. Tumor-bearing mice were treated with CMG017 per os, either alone or in combination with immune checkpoint inhibitors (ICIs). The tumor microenvironment (TME) was assessed through histological, flow-cytometric, and Nanostring immune profiling analyses. Results: CMG017 suppressed kynurenine production more effectively than inhibitors targeting either IDO or TDO alone, in various human and murine cancer cell lines. Single administration of CMG017 showed favorable pharmacokinetic profiles compared with an IDO1 selective inhibitor. Repeated once-daily per os administration of CMG017 decreased kynurenine concentration in both tumors and plasma of tumor-bearing mice and delayed tumor growth without significant toxicity. CMG017 induced dramatic changes in immune-related genes in TME and enhanced intratumoral infiltration of CD8+ effector T cells. The anti-tumor activity of CMG017 was almost negated when T cells were depleted, indicating the importance of adaptive immunity for the in vivo efficacy of CMG017. Of note, combination immunotherapy of CMG017 with ICIs (anti-PD-1 and anti-CTLA-4) led to durable tumor regression and long-term overall survival. Mice with complete tumor regression were immune to tumor re-challenge, indicating the establishment of immunological memory. Conclusions: CMG017, a dual inhibitor of IDO and TDO, potently suppressed the kynurenine pathway and showed promising anti-cancer efficacy, with favorable pharmacologic profiles.
4
Campesato, Luis Felipe, Sadna Budhu, Jeremy Tchaicha, Abhinav Jaiswal, Mathieu Gigoux, Stephane Pourpe, Cailian Liu, et al. "Blockade of IDO/TDO downstream effectors restricts cancer immune suppression." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 137.3. http://dx.doi.org/10.4049/jimmunol.202.supp.137.3.
Анотація:
Abstract Immune checkpoint blockade (ICB) results in clinical benefit for a subset of cancer patients, yet multiple mechanisms of resistance can impair optimal response. The catabolism of tryptophan into metabolites known as kynurenines (Kyn) by the expression of enzymes such as IDO or TDO is a frequent phenomenon that plays a suppressive role in tumor immunity. Recently it was shown that Kyn acts as agonist of the aryl hydrocarbon receptor (AHR). Here we sought to characterize the mechanisms of immune suppression associated with the AHR pathway and to evaluate its potential as therapeutic target. RNAseq analysis of human cancers revealed a correlation between the expressions of AHR-related genes with markers associated with immunotherapy resistance (PD-1, FOXP3, CD206). By using IDO or TDO-overexpressing variants of a melanoma cell model (B16-F10), we found that myeloid cells, such as tumor-associated macrophages (TAMs) and dendritic cells (DCs), present up-regulation of the AHR. IDO-expressing tumors (B16-IDO) show higher myeloid cell infiltration, which present a tolerogenic phenotype. Tumor-antigen specific CD8T cells present reduced expression of activation markers and proliferation rate when primed by Kyn-treated BMDCs. Treatment of B16-IDO-bearing mice with an AHR-specific antagonist (CH-223191) leads to an increase of MHC II in TAMs, of activation markers in CD8 T cells and reduced frequency of T-regs. AHR inhibition delays progression of tumors with an active IDO/TDO/Kyn pathway (B16-IDO and B16-TDO), and efficacy is further improved when ICB is used in combination. In summary, our findings demonstrate that targeting the Kyn pathway through AHR inhibition could overcome key suppressive mechanisms and sensitize tumors to ICB.
5
Thackray, Sarah J., Christopher G. Mowat, and Stephen K. Chapman. "Exploring the mechanism of tryptophan 2,3-dioxygenase." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1120–23. http://dx.doi.org/10.1042/bst0361120.
Анотація:
The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes.
6
Oxenkrug, G. "Genetic and Environmental Impacts in Major Depressive Disorder are Mediated Via Kynurenine Pathway of Tryptophan Metabolism." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70899-5.
Анотація:
We were first to propose up-regulation of KYN pathway of TRY metabolism as an etiological factor in depression: “in depression metabolism of TRY is shunted away from serotonin production, and towards KYN production” since “activity of liver TRY-pyrrolase is stimulated by raised blood corticosteroids levels” (Lapin & Oxenkrug, Lancet, 1969). TRY-pyrrolase, i.e., tryptophan-2,3-dioxygenase (TDO) was the only known enzyme catalyzing TRY conversion into KYN. TDO is mostly located in liver and activated by cortisol and prolactin. Seven years later another enzyme catalyzing TRY conversion into KYN, indoleamine-2,3-dioxygenase (IDO), was discovered. IDO is located in microglia, astrocytes and macrophages, and transcriptionally induced by pro-inflammatory cytokines. Discovery of neurotropic activity of kynurenines suggested that upregulation of TRY - KYN pathway not only augments serotonin deficiency but also underlines depression-associated anxiety, psychosis and cognitive decline. Simultaneous presence of high promoters alleles of pro-inflammatory cytokines genes (IFNG and TNF-alpha) determines genetic predisposition to depression via up-regulation of IDO while impact of environmental stresses is mediated via hormonal activation of TDO. Potentiation of IFNG-induced up-regulation of IDO by stress hormones further underscores the importance TRY-KYN pathway as major meeting point of gene-environment interaction in depression and as a new target for pharmacological intervention.
7
SUZUKI, Sachiko, Shigenobu TONÉ, Osamu TAKIKAWA, Toshikazu KUBO, Ichiro KOHNO, and Yohsuke MINATOGAWA. "Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti." Biochemical Journal 355, no. 2 (April 6, 2001): 425–29. http://dx.doi.org/10.1042/bj3550425.
Анотація:
Indoleamine 2,3-dioxygenase (IDO)-initiated tryptophan degradation in the placenta has been implicated in the prevention of the allogeneic fetus rejection [Munn, Zhou, Attwood, Bondarev, Conway, Marshall, Brown, and Mellor (1998) Science 281, 1191-1193]. To determine how IDO is associated with the development of the fetus and placenta, the time course of IDO expression (tryptophan-degrading activity, IDO protein and IDO mRNA) in the embryonic and extra-embryonic tissues as well as maternal tissues of mice was examined. A high tryptophan-degrading activity was detected in early concepti on days 6.5 and 7.5, whereas IDO protein and its mRNA were not expressed during early gestation, but appeared 2-3 days later, lasted for about 3 days and declined rapidly thereafter. The expression of IDO basically coincided with the formation of the placenta. On the contrary, the early tryptophan-degrading activity was due to gene expression of tryptophan 2,3-dioxygenase (TDO), as shown by Northern and Western analysis. These findings indicate that IDO is transiently expressed in the placenta but that the expression does not last until birth, and that the IDO expression is preceded by expression of another tryptophan-degrading enzyme, TDO, in the maternal and/or embryonic tissues in early concepti.
8
Nienhaus, Karin, and G. Ulrich Nienhaus. "Co Recombination in Human IDO and TDO - A Comparison." Biophysical Journal 106, no. 2 (January 2014): 676a. http://dx.doi.org/10.1016/j.bpj.2013.11.3744.
9
Sacramento, Jireh Joy D., and David P. Goldberg. "Oxidation of an indole substrate by porphyrin iron(iii) superoxide: relevance to indoleamine and tryptophan 2,3-dioxygenases." Chemical Communications 56, no. 20 (2020): 3089–92. http://dx.doi.org/10.1039/c9cc10019a.
Анотація:
Reaction of FeIII(O2˙−)(TPP) with 2,3-dimethylindole at low temperature leads to the ring-cleaved, dioxygenated product, N-(2-acetyl-phenyl)-acetamide, analogous to TDO/IDO enzymes.
10
Paccosi, Sara, Marta Cecchi, Angela Silvano, Sergio Fabbri, and Astrid Parenti. "Different effects of tryptophan 2,3-dioxygenase inhibition on SK-Mel-28 and HCT-8 cancer cell lines." Journal of Cancer Research and Clinical Oncology 146, no. 12 (August 10, 2020): 3155–63. http://dx.doi.org/10.1007/s00432-020-03351-2.
Анотація:
Abstract Purpose Indoleamine 2,3-dioxygenase-1 (IDO1) and more recently, tryptophan 2,3-dioxygenase (TDO), are tryptophan-catabolizing enzymes with immunoregulatory properties in cancer. IDO1 is more expressed than TDO in many tumours including melanomas; however, IDO inhibitors did not give expected results in clinical trials, highlighting the need to consider TDO. We aimed to characterize both TDO expression and function in a melanoma cell line, named SK-Mel-28, with the purpose to compare it with a colon cancer cell line, HCT-8, and with a human endothelial cell line (HUVEC). Methods TDO expression was assessed as real time-PCR and western blot, for mRNA and protein expression, respectively. While cell proliferation was assessed as cell duplication, cell apoptosis and cell cycle were analysed by means of flow cytometry. Results SK-Mel-28 cells showed higher TDO levels compared to HCT-8 and to HUVEC cells. A selective TDO inhibitor, 680C91, significantly impaired cell proliferation in a concentration-dependent manner, by inducing cell arrest during the G2 phase for SK-Mel-28 and HUVEC cells, while an early apoptosis was increasing in HCT-8 cells. No toxic effects were observed. These data demonstrated that TDO is highly expressed in SK-Mel-28 cells and may be involved in the regulation of their proliferation. Conclusion TDO may directly modulate cancer cell function rather than immune suppression and can be considered as a target for melanoma progression together with IDO1.
11
Funakoshi, Hiroshi, Masaaki Kanai, and Toshikazu Nakamura. "Modulation of Tryptophan Metabolism, Promotion of Neurogenesis and Alteration of Anxiety-Related Behavior in Tryptophan 2,3-Dioxygenase-Deficient Mice." International Journal of Tryptophan Research 4 (January 2011): IJTR.S5783. http://dx.doi.org/10.4137/ijtr.s5783.
Анотація:
Although tryptophan (Trp) and its metabolites, such as serotonin (5-HT) and kynurenines (KYNs), are strong modulators of emotional behavior, the metabolic pathway(s) responsible for this physiological modulation is not fully understood. Two of the initial rate-limiting enzymes of the kynurenine pathway for Trp metabolism are known: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Based on our comparison of tdo-deficient ( Tdo–/–) mice with their wild-type littermates, we report that TDO is the physiological modulator of systemic Trp, brain Trp and serotonin (5-HT), and, therefore, anxiety-related behavior. Tdo–/– mice showed increased plasma concentrations of Trp (about 10-fold) and its metabolites 5-hydroxyindoleacetic acid (5-HIAA) and kynurenine, as well as increased levels of Trp (about 20-fold), 5-HT and 5-HIAA in the hippocampus and midbrain. The Tdo–/– mice also showed anxiolytic modulation in the elevated plus maze and open field tests, and increased neurogenesis during adulthood, as evidenced by double staining with 5-bromo-2‘-deoxyuridine (BrdU) and neural progenitor/neuronal markers. TDO also plays a role in the maintenance of brain morphology in adult animals by regulating neurogenesis in the hippocampus and subventricular zone. Collectively, our results in Tdo–/– mice indicate a direct molecular link between Trp metabolism and mental status in mice. Tdo–/– mice will likely prove useful both in identifying the physiological role of Trp metabolism in normal brain function and in psychiatric disorders and in developing new therapeutic interventions for mental disorders. In addition, the potential role(s) and molecular mechanisms of TDO in metabolic mental disease(s) and in emotional behavior are discussed.
12
Badawy, Abdulla A.-B. "Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects." International Journal of Tryptophan Research 10 (January 1, 2017): 117864691769193. http://dx.doi.org/10.1177/1178646917691938.
Анотація:
Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 “vitamin” nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.
13
Yoshioka, Saeko, Tomonori Ikeda, Sogo Fukuchi, Yurika Kawai, Katsumi Ohta, Hisashi Murakami, Naohisa Ogo, Daisuke Muraoka, Osamu Takikawa, and Akira Asai. "Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase." International Journal of Tryptophan Research 15 (January 2022): 117864692211384. http://dx.doi.org/10.1177/11786469221138456.
Анотація:
Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO. Characterization of this cell line using kinase inhibitor library resulted in identification of MEK/ERK pathway-dependent TDO expression. After knowing the properties for TDO expression, we further proceeded to screen chemical library for TDO inhibitors. We previously determined that S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an important pharmacophore for binding to heme. Based on this premise, we screened an in-house library composed of various isothiourea derivatives and identified a bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly, PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and cell-free assays but did not inhibit other heme enzymes. Molecular docking studies suggested the importance of isothiourea moieties at the ortho position of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed competitive inhibition against TDO, and this was supported by the docking simulation. PVZB3001 recovered natural killer (NK) cell viability and functions by inhibiting Kyn accumulation in conditioned medium of both IDO1- and TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn production assay with a glioblastoma cell line. This inhibitor could be a useful pharmacological tool for modulating the Kyn pathway in a variety of experimental systems.
14
Badawy, Abdulla A.-B., and Gilles J. Guillemin. "Species Differences in Tryptophan Metabolism and Disposition." International Journal of Tryptophan Research 15 (January 2022): 117864692211225. http://dx.doi.org/10.1177/11786469221122511.
Анотація:
Major species differences in tryptophan (Trp) metabolism and disposition exist with important physiological, functional and toxicity implications. Unlike mammalian and other species in which plasma Trp exists largely bound to albumin, teleosts and other aquatic species possess little or no albumin, such that Trp entry into their tissues is not hampered, neither is that of environmental chemicals and toxins, hence the need for strict measures to safeguard their aquatic environments. In species sensitive to toxicity of excess Trp, hepatic Trp 2,3-dioxygenase (TDO) lacks the free apoenzyme and its glucocorticoid induction mechanism. These species, which are largely herbivorous, however, dispose of Trp more rapidly and their TDO is activated by smaller doses of Trp than Trp-tolerant species. In general, sensitive species may possess a higher indoleamine 2,3-dioxygenase (IDO) activity which equips them to resist immune insults up to a point. Of the enzymes of the kynurenine pathway beyond TDO and IDO, 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase (ACMSD) determines the extent of progress of the pathway towards NAD+ synthesis and its activity varies across species, with the domestic cat ( Felis catus) being the leading species possessing the highest activity, hence its inability to utilise Trp for NAD+ synthesis. The paucity of current knowledge of Trp metabolism and disposition in wild carnivores, invertebrates and many other animal species described here underscores the need for further studies of the physiology of these species and its interaction with Trp metabolism.
15
Yeh, Syun-Ru, Ariel Lewis-Ballester, and Shay Karkashon. "Comparative Studies of Human Indoleamine 2,3-Dioxygenase (IDO) and Tryptophan Dioxygenase (TDO)." Biophysical Journal 102, no. 3 (January 2012): 467a. http://dx.doi.org/10.1016/j.bpj.2011.11.2560.
16
Takkenkamp, Tim J., Mathilde Jalving, Frederik J. H. Hoogwater, and Annemiek M. E. Walenkamp. "The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors." Endocrine-Related Cancer 27, no. 9 (September 2020): R329—R343. http://dx.doi.org/10.1530/erc-20-0113.
Анотація:
Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration, and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review, we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response.
17
Luques, Lisandro, Ashby Kissoondoyal, Emily De Sousa, Paula Quaglietta, David Malkin, Stefano Cairo, Emilie Indersie, and Reto Baertschiger. "Abstract 3539: Indoleamine-2,3-dioxygenase 2 (IDO-2) is expressed in hepatoblastoma cells and associated with metastatic state." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3539. http://dx.doi.org/10.1158/1538-7445.am2023-3539.
Анотація:
Abstract Hepatoblastoma (HB) is the most common pediatric primary liver malignancy and represents about 1% of all pediatric tumors. Incidence of HB has been increasing in the past 10 years. Risk stratification of HB patients is established by the extent of the liver disease, patient age, levels of serum AFP and presence of metastatic disease. Currently, treatment and prognosis of HB patients relies on chemotherapy and complete tumor resection. Unfortunately, patients with high-risk HB (metastatic, unresectable, refractory and recurrent) have dismal prognosis. The molecular mechanisms underlying the aggressiveness and metastatic potential of the tumor have not been elucidated yet. Tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase 1 and 2 (IDO 1 and IDO-2) are enzymes in mammals that catabolize tryptophan to kynurenine and its activity has been related with immunoregulation and tumorigenesis. While TDO and IDO-1 have been extensively studied before the discovery of IDO-2, the role of the later in tumorigenesis is still under evaluation. Expression of IDO-2 is normally found in liver, kidney, pancreas, brain and epididymis while a dysregulated expression was reported in different types of cancer. IDO-2 activity was found to affect both the immune cells activation status and also the proliferation, migration and survival of tumor cells both in vitro and in vivo. Despite being expressed in normal liver tissues, IDO-2 expression has never been assessed in HB cells. The aim of this study was to determine if IDO-2 mRNA is expressed in HB cell lines and to determine if this expression is correlated with patient risk classification. By using real-time RT-PCR, we determined the expression of IDO-2 in commercially available HepG2 cells and in three patient derived xenograft (PDX)-derived HB cell lines (HB214, HB279, HB 303) (high risk metastatic, high-risk non metastatic and-low risk, respectively). IDO-2 is expressed in both HepG2 cells and in the 3 PDX-derived cell lines. Data analysis by using linear mixed effects modelling followed by t-tests to examine specific comparisons showed significant differences between cell lines. Expression of IDO-2 in cells from the metastatic tumor (HB214) was significantly higher than in HepG2 and cells from non-metastatic disease (p<0.05). In conclusion, we report here for the first time that IDO-2 is expressed in HB cells. Although further investigation should be conducted in order to understand its specific role in HB, the findings in this work suggest that IDO-2 expression might be related with clinical tumor behavior. Citation Format: Lisandro Luques, Ashby Kissoondoyal, Emily De Sousa, Paula Quaglietta, David Malkin, Stefano Cairo, Emilie Indersie, Reto Baertschiger. Indoleamine-2,3-dioxygenase 2 (IDO-2) is expressed in hepatoblastoma cells and associated with metastatic state. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3539.
18
Qin, Yanjie, Nanxi Wang, Xinlin Zhang, Xuemei Han, Xuejia Zhai, and Yongning Lu. "IDO and TDO as a potential therapeutic target in different types of depression." Metabolic Brain Disease 33, no. 6 (July 16, 2018): 1787–800. http://dx.doi.org/10.1007/s11011-018-0290-7.
19
Muzik, O., F. John, S. Mittal, and C. Juhasz. "P11.35 Fluorine-18-labeled PET radiotracers for imaging tryptophan uptake and metabolism in brain tumors." Neuro-Oncology 21, Supplement_3 (August 2019): iii50—iii51. http://dx.doi.org/10.1093/neuonc/noz126.181.
Анотація:
Abstract BACKGROUND Abnormal metabolism of tryptophan via the serotonin and kynurenine pathways plays a key role in multiple disease processes including cancer. Upregulation of key enzymes of the kynurenine pathway (such as indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]) plays an important role in immune resistance in human brain tumors. IDO inhibitors have recently entered in human clinical trials, and their use can benefit from molecular imaging evaluating IDO activity. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative PET radiotracers. Human studies with such tracers showed promise but have been confined to carbon-11-labeled compounds (such as alpha-[11C]methyl-L-tryptophan). Preclinical development of fluorine-18-labeled tryptophan-based radiotracers has surged only in recent years. We performed a systematic review of studies reporting on such tracers and summarized their biological characteristics and their potential for imaging key enzymes of the kynurenine pathway. MATERIAL AND METHODS A PubMed search using the key words “tryptophan” and “PET”/”positron emission tomography” was performed. English language original articles including data on the preparation and/or radiochemical or biological characteristics of fluorine-18-labeled tryptophan derivative radiotracers have been reviewed. RESULTS Nineteen original papers identified by the search included data on 15 unique fluorine-18-labeled tryptophan-derived radiotracers. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer among the 15. Biodistribution studies showed high uptake in the pancreas, and the L-type amino acid transporter was the dominant transport mechanism for most of the reported radiotracers. Multiple tracers showed accumulation in various tumor cell lines, including glioma cell lines, in vitro and in xenografts in vivo, with favorable tumor-to-background uptake ratios in comparison to clinically used fluorine-18-labeled radiotracers (such as glucose and non-tryptophan amino acid analogs). Five of the 15 tracers showed promise for imaging IDO activity, including a fluorine-18-labeled analog of alpha-[11C]methyl-L-tryptophan. Two of the 15 radiotracers were metabolized by TDO but showed rapid defluorination in vivo. CONCLUSION Most fluorine-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several of these radiotracers show promise for imaging IDO activity in vivo, and, therefore, could be leading candidates for testing and validation toward human tumor PET imaging applications.
20
Ye, Zixiang, Linxiu Yue, Jiachen Shi, Mingmei Shao, and Tao Wu. "Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications." Journal of Cancer 10, no. 12 (2019): 2771–82. http://dx.doi.org/10.7150/jca.31727.
21
Jovanovic, Filip, Kenneth D. Candido, and Nebojsa Nick Knezevic. "The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents." International Journal of Molecular Sciences 21, no. 17 (August 22, 2020): 6045. http://dx.doi.org/10.3390/ijms21176045.
Анотація:
Tryptophan (TRP) is an essential, aromatic amino acid catabolized by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) enzymes into kynurenine. The IDO enzyme is expressed in peripheral tissues and the central nervous system. Another enzyme of interest in the kynurenine signaling pathway is kynurenine 3-monooxygenase (KMO). The purpose of this review is to discuss the role of TRP and the kynurenine signaling pathway in different chronic pain patients. The IDO-1, IDO-2, and KMO enzymes and the kynurenine metabolite have been shown to be involved in the pathogenesis of neuropathic pain and other painful conditions (migraine, cluster headache, etc.) as well as depressive behavior. We highlighted the analgesic potential of novel agents targeting the enzymes of the kynurenine signaling pathway to explore their efficacy in both future basic science and transitional studies. Upcoming studies conducted on animal models will need to take into consideration the differences in TRP metabolism between human and non-human species. Since chronic painful conditions and depression have common pathophysiological patterns, and the kynurenine signaling pathway is involved in both of them, future clinical studies should aim to have outcomes targeting not only pain, but also functionality, mood changes, and quality of life.
22
Naismith, James H. "Tryptophan oxygenation: mechanistic considerations." Biochemical Society Transactions 40, no. 3 (May 22, 2012): 509–14. http://dx.doi.org/10.1042/bst20120073.
Анотація:
From a protein structural viewpoint, tryptophan is often considered an inert structural amino acid, playing a role as a hydrophobic anchor in membrane proteins or as part of the hydrophobic core of soluble proteins. However, tryptophan is the only polyaromatic amino acid and, from a chemical viewpoint, possesses unique reactivity owing to the electron-richness of the indole system. This reactivity is seen in the area of natural products and metabolites which have exquisite modifications of the indole ring system. Enzymes have evolved multiple strategies to break or modify the indole ring; one particular class is the IDO/TDO (indoleamine/tryptophan dioxygenase) superfamily. A new member of this family, PrnB, on the surface catalyses a very different reaction, but actually shares much of the early chemistry with the tryptophan dioxygenases. Studies on PrnB have contributed to our understanding of the wider superfamily. In the present mini-review, recent developments in our understanding of how the TDO class of enzymes use activated molecular oxygen to break the indole ring are discussed.
23
Ashoura, Norah E., Joseph D. Dekker, Todd Triplett, Kendra Garrison, John Blazeck, Christos Karamitros, Candice Lamb, et al. "The Force Awakens: Illuminating the role of kynurenine in cancer progression and treatment." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 177.3. http://dx.doi.org/10.4049/jimmunol.200.supp.177.3.
Анотація:
Abstract Cancer is the second leading cause of death in the US and, despite progress in treatment options, there is a critical need for novel treatments that specifically target cancerous cells. Our immune system routinely identifies potential cancer cells and eliminates them without the need for clinical intervention. However, to evade immune clearance, many cancers elevate tryptophan catabolism in the tumor microenvironment (TME) by upregulating the enzymes indoleamine 2, 3-dioxygenase (IDO) or, alternatively, tryptophan 2, 3- dioxygenase (TDO). This results in greater tryptophan turnover, accumulation of IDO/TDO product, kynurenine (L-kyn), and immune suppression in the TME. Whether the resulting immunosuppression arises from tryptophan depletion or L-kyn accumulation remains highly controversial. This work aims to (1) clarify L-kyn’s effect on T-cells and (2) whether its depletion can relieve tumor burden. Exposing T cells to L-kyn in vitro results in gene expression changes consistent with regulatory T-cell generation and the suppression of naïve T-cell proliferation; establishing L-kyn as a key therapeutic target for depletion to relieve TME immune suppression. Using a pharmacologically optimized kynureninase (KynU) enzyme, we tested L-kyn depletion therapy in murine cancers. KynU administration potently inhibits tumor growth, reduces L-kyn concentration, and results in a significant increase in the infiltration and proliferation of polyfunctional T-lymphocytes. Our ongoing study of KynU’s efficacy and L-kyn’s in vitro effects will illuminate details of L-kyn’s elusive mechanism of action, resolving critical mechanisms of tumor tolerance while creating a more innovative and effective cancer treatment strategy.
24
Rafice, Sara A., Nishma Chauhan, Igor Efimov, Jaswir Basran, and Emma Lloyd Raven. "Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase." Biochemical Society Transactions 37, no. 2 (March 20, 2009): 408–12. http://dx.doi.org/10.1042/bst0370408.
Анотація:
The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.
25
Badawy, Abdulla A.-B., and Gilles Guillemin. "The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal." International Journal of Tryptophan Research 12 (January 2019): 117864691986897. http://dx.doi.org/10.1177/1178646919868978.
Анотація:
The plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio is frequently used to express or reflect the activity of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO). This ratio is increasingly used instead of measurement of IDO activity, which is often low or undetectable in immune and other cells under basal conditions, but is greatly enhanced after immune activation. The use of this ratio is valid in in vitro studies, eg, in cell cultures or isolated organs, but its ‘blanket’ use in in vivo situations is not, because of modulating factors, such as supply of nutrients; the presence of multiple cell types; complex structural and functional tissue arrangements; the extracellular matrix; and hormonal, cytokine, and paracrine interactions. Determinants other than IDO may therefore be involved in vivo. These are hepatic tryptophan 2,3-dioxygenase (TDO) activity and the flux of plasma-free Trp down the Kyn pathway. In addition, conditions leading to accumulation of Kyn, eg, inhibition of activities of Kyn monooxygenase and kynureninase, could lead to elevation of the aforementioned ratio. In this review, the origin of use of this ratio will be discussed, variations in extent of its elevation will be described, evidence against its indiscriminate use will be presented, and examining determinants other than IDO activity and their correlates will be proposed for future studies.
26
Oh, Angela. "Crystallization of heme dioxygenases IDO and TDO facilitates structure-based design of cancer immunology therapeutics." Acta Crystallographica Section A Foundations and Advances 76, a1 (August 2, 2020): a45. http://dx.doi.org/10.1107/s0108767320099547.
27
Campesato, Luis Felipe, Sadna Budhu, Jeremy Tchaicha, Stephane Pourpe, Cailian Liu, Mark G. Manfredi, Karen McGovern, Jedd D. Wolchok, and Taha Merghoub. "Interaction between Kynurenine and the AhR is an effector mechanism of tumor immunosuppression and represents a potential immunotherapy target." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 177.5. http://dx.doi.org/10.4049/jimmunol.200.supp.177.5.
Анотація:
Abstract Although with notable impact on cancer treatment, immune-checkpoint blockade (ICB) have multiple mechanisms of resistance. The catabolism of Tryptophan into metabolites known as Kynurenines (Kyn) by enzymes such as IDO or TDO plays a major suppressive role in different tumor types. Recently it was shown that Kyn acts as an endogenous agonist of the Aryl-hydrocarbon Receptor (AhR). In order to gain a better understanding of this pathway, we sought to characterize the mechanisms of immunosuppression associated with AhR and evaluate its potential as therapeutic target. Gene-expression analysis of IDO-overexpressing melanomas (B16-IDO vs B16-WT) present reduced expression levels of Type-1 inflammatory genes, including IFNy, TNFa, Granzyme B and CD40. In addition, B16-IDO presents higher infiltration of TAMs, which up-regulate classic AhR-regulated genes (Cyp1a1 and Cyp1b1) and are differentially skewed towards an immunosuppressive M2-phenotype. Tumor-antigen specific CD8+T cells present reduced expression of activation markers (GzmB and CD44) and proliferation rate when primed by Kyn-treated BMDMs. Also, B16-IDO TAMs suppressed activation of CD8+T cells in vitro and their depletion abrogated tumor growth. Implantation of B16-IDOs in FoxP3-depleted mice prevents TAMs accumulation. Treatment of B16-IDO tumors with an AhR-specific antagonist (CH-223191) up-regulates MHC II in APCs, activation markers in CD8s and reduced frequency of T-regs. AhR inhibition slows down tumor growth and prolongs survival, which is improved in combination with PD-1 blockade. In summary, our findings demonstrate that targeting the Kyn pathway through AhR-inhibition represents a promising approach in cancer patients who are resistant to ICB.
28
Alan, Wise, Mcguinness E. Barry, Cowley M. Phillip, Trewick C. Sarah, Bevan Nicola, Szybut Clare, and Brown J. Thomas. "ITOC2 – 013. In vitro kynurenine modulation by novel dual-acting and selective TDO and IDO inhibitors." European Journal of Cancer 51 (March 2015): S5. http://dx.doi.org/10.1016/j.ejca.2015.01.026.
29
Yuasa, Hajime J., and Helen J. Ball. "Efficient tryptophan-catabolizing activity is consistently conserved through evolution of TDO enzymes, but not IDO enzymes." Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 324, no. 2 (February 20, 2015): 128–40. http://dx.doi.org/10.1002/jez.b.22608.
30
Badawy, Abdulla A. B., Aryan M. A. Namboodiri, and John R. Moffett. "The end of the road for the tryptophan depletion concept in pregnancy and infection." Clinical Science 130, no. 15 (June 29, 2016): 1327–33. http://dx.doi.org/10.1042/cs20160153.
Анотація:
We hypothesize that: (1) L-tryptophan (Trp) is greatly utilized and not depleted in pregnancy; (2) fetal tolerance is achieved in part through immunosuppressive kynurenine (Kyn) metabolites produced by the flux of plasma free (non-albumin-bound) Trp down the Kyn pathway; (3) the role of indoleamine 2,3-dioxygenase (IDO) in infection is not related to limitation of an essential amino acid, but is rather associated with stress responses and the production of Kyn metabolites that regulate the activities of antigen presenting cells and T-cells, as well as increased NAD+ synthesis in IDO-expressing cells; (4) Trp depletion is not a host defence mechanism, but is a consequence of Trp utilization. We recommend that future studies in normal and abnormal pregnancies and in patients with infections or cancer should include measurements of plasma free Trp, determinants of Trp binding (albumin and non-esterified fatty acids), total Trp, determinants of activities of the Trp-degrading enzymes Trp 2,3-dioxygenase (TDO) (cortisol) and IDO (cytokines) and levels of Kyn metabolites. We also hypothesize that abnormal pregnancies and failure to combat infections or cancer may be associated with excessive Trp metabolism that can lead to pathological immunosuppression by excessive production of Kyn metabolites. Mounting evidence from many laboratories indicates that Trp metabolites are key regulators of immune cell behaviour, whereas Trp depletion is an indicator of extensive utilization of this key amino acid.
31
El-Zahabi, Mohamed Ayman ALy, Mostafa Youssef Abouzeid, Ibrahim H. Eissa, and Mohamed S. Taghour. "DUAL INHIBITORS OF INDOLEAMINE-2,3-DIOXYGENASE (IDO) AND TRYPTOPHAN-2,3-DIOXYGENASE (TDO) AS ANTI-TUMOR IMMUNE MODULATORS." Al-Azhar Journal of Pharmaceutical Sciences 69, no. 1 (March 1, 2024): 38–61. http://dx.doi.org/10.21608/ajps.2024.360357.
32
Kim, C., N. K. Lee, J. S. Kim, W. R. Kim, D. H. Kim, D. J. Kim, J. S. Oh, S. K. Chang, J. W. Kim, and H. J. Chon. "An oral dual inhibitor of IDO and TDO enhances anti-cancer immunity and synergizes with immune checkpoint blockade." Annals of Oncology 29 (October 2018): viii416. http://dx.doi.org/10.1093/annonc/mdy288.039.
33
Liu, Xiangdong, Niu Shin, Holly K. Koblish, Gengjie Yang, Qian Wang, Kathy Wang, Lynn Leffet, et al. "Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity." Blood 115, no. 17 (April 29, 2010): 3520–30. http://dx.doi.org/10.1182/blood-2009-09-246124.
Анотація:
Abstract Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.
34
Brincks, Erik L., James Adams, Lifu Wang, Benjamin Turner, Agnieszka Marcinowicz, Jiyuan Ke, Michael Essmann, et al. "Indoximod opposes the immunosuppressive effects mediated by IDO and TDO via modulation of AhR function and activation of mTORC1." Oncotarget 11, no. 25 (June 23, 2020): 2438–61. http://dx.doi.org/10.18632/oncotarget.27646.
35
Berthon, Céline, Michaela Fontenay, Selim Corm, Isabelle Briche, Michel Lhermitte, and Bruno Quesnel. "Metabolites of Tryptophan Catabolism Are Elevated in Sera of Patients with Myelodysplastic Syndromes and Inhibit Hematopoietic Progenitor Amplification." Blood 120, no. 21 (November 16, 2012): 3843. http://dx.doi.org/10.1182/blood.v120.21.3843.3843.
Анотація:
Abstract Abstract 3843 Introduction: Tryptophan catabolism, which is mediated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), produces kynurenine, which blocks T-cell activation and induces immunosuppression. Kynurenine itself is converted by downstream enzymes into secondary catabolites that also have toxic effects on T cells. Tryptophan catabolism is elevated in many cancers, including acute myeloid leukemia (AML). However, tryptophan catabolites that are downstream of kynurenine have never been investigated in hematological malignancies. Methods: We evaluated the serum levels of primary and secondary tryptophan catabolites in a cohort of patients with myelodysplastic syndromes (MDS). Sera were isolated from 132 adult MDS patients after informed consent was obtained in accordance with the Helsinki Declaration. The levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and anthranilic acid in the sera were quantified using HPLC. For erythroid cell expansion, CD34+ cells were collected and isolated from the mononuclear cell fractions of cytapheresis products from 3 healthy donors and cultured in liquid medium under erythroid conditions with tryptophan catabolites. Results: The MDS patients showed significantly lower levels of tryptophan and higher levels of kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and anthranilic acid compared with the healthy controls. We also compared the kynurenine and tryptophan levels in the MDS patients with our previous cohort of 112 patients with primary AML. The kynurenine/tryptophan ratios were significantly higher in the MDS patients (median 0.0468 vs. 0.0676). The tryptophan catabolites correlated with cytopenia; higher kynurenine levels were associated with lower hemoglobin levels and higher blast counts and were associated with presence of dysgranulopoiesis. Lower tryptophan levels were found in patients with platelet transfusion dependency. Kynurenic acid levels were higher in patients with dysmegakaryopoiesis. High 3-hydroxyanthranilic and kynurenic acid levels were associated with severe thrombopenia below 20 G/L. IPSS score, cytogenetic, and WHO diagnosis did not associated with any tryptophan catabolite level. The tryptophan catabolites inhibited progenitor expansion during the in vitro culture of hematopoietic cells and reduced the numbers of granulocytes and erythroblasts. Conclusions: Thus, MDS patients are characterized by high tryptophan catabolism resulting in elevated primary and secondary metabolites, which both have inhibitory effects on hematopoiesis. These results suggest that IDO or TDO inhibitors should be investigated in MDS. Disclosures: No relevant conflicts of interest to declare.
36
Petrovic, Vladimir, Jamie Wong, Cedric E. Dos Santos, Richard Smith, Dan Fitzpatrick, Robert Loberg, and Ariel Avilion. "IDO Pathway Analysis for Identifying Novel Biomarkers in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 5572. http://dx.doi.org/10.1182/blood-2018-99-111392.
Анотація:
Abstract Background: Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial rate-limiting step in Tryptophan (Trp) degradation along the Kynurenine pathway. Trp can be catabolized by tryptophan hydroxylase into serotonin (Ser) or alternatively, by IDO and tryptophan-2,3-dioxygenase (TDO) into Kynurenine (Kyn). A variety of human tumors have been shown to express an active IDO which leads to the induction of immune tolerance and malignant cell survival (Mellor et al, 1999). Elevated IDO activity within tumor microenvironment impairs the function of antigen specific T cells and suppresses the anti-tumor immune response, while in tumor-draining lymph nodes an active IDO inhibits the antigen presentation reducing the population of antigen-specific T cells and stimulates regulatory T cells (Treg) activation (Curti et al. 2009). IDO overexpression has been correlated with poor prognosis in a number of human solid tumors including ovarian, endometrial and colon carcinoma (Okamoto et al. 2005, Ino et al. 2006, Brandacher et al. 2006). In hematological malignancies, such as AML and DLBCL, IDO expression has also shown significant prognostic value (Folgiero et al. 2014, Ninomiya et al. 2011). Currently, our understanding of the role of IDO in multiple myeloma (MM) is limited to a few existing studies correlating the abundance of selected IDO pathway metabolites with the disease (Bonanno et al. 2012, Zdzisinska et al. 2010). We hypothesize that IDO activity correlates with the disease onset and progression in MM patients. Methods: We quantified the levels of Trp, Kyn, and Ser in human serum by mass spectrometry using the Biocrates AbsoluteIDQ p180 kit. Analysis was performed using MetaboAnalyst 3.0 and Graphpad prism software. The serum samples derived from healthy donors and MM patients were obtained commercially. Results: We found significantly reduced levels of Trp (n=13, p<0.001) and elevated levels of Kyn (n=13, p<0.05) in serum samples from MM patients compared to matching (sex and age paired) healthy donor samples, while Ser levels did not differ significantly. Similarly, samples obtained from Newly Diagnosed (ND) MM patients showed a significant reduction in Trp (n=16, p<0.01) and a trend towards increased Kyn. The overall results in Relapsed/Refractory (R/R) MM patients were similar to the ND setting, although we only detected a trend towards Trp reduction, and observed a significant increase in Kyn levels (n=26, p<0.01) when compared to healthy donors. These results were confirmed when analyzing the data using the widely employed Kyn/Trp ratio, a potential marker for assessing IDO activity. A significantly elevated Kyn/Trp ratio was observed in all of the MM malignant populations (paired: n=13, p<0.001; ND: n=16, p<0.01; R/R: n=26, p<0.01) as compared to healthy individuals. Conclusions: Our study suggests that increased activity of IDO, and/or the production of downstream metabolites is one of the features of MM, and could potentially define a valuable set of novel biomarkers. Here we show a consistent pattern of increased Kyn and decreased Trp levels as well as an elevated Kyn/Trp ratio, all of which are hallmarks of high IDO activity in MM subjects when compared to healthy individuals. We did not detect any significant differences in Ser levels between any of the groups which may suggest that the catabolic pathway is not dependent on tryptophan hydroxylase. Additional studies are being initiated to further investigate the role of IDO/Trp pathway in MM pathogenesis as well as better understand its potential prognostic and predictive impact in currently used MM therapies. Disclosures No relevant conflicts of interest to declare.
37
Booth, Nicholas, Wells Brockbank, Samuel Oh, and Karl Kingsley. "Indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase (TDO) mRNA expression in oral squamous cell carcinoma cells is actively and differentially modulated." Journal of Molecular Pathophysiology 1, no. 1 (2012): 29. http://dx.doi.org/10.5455/jmp.20120609040915.
38
Chen, Xiangli, Yuzhu Zang, Dujuan Li, Jianmin Guo, Yacai Wang, Yuqi Lin, and Zhenghong Wei. "IDO, TDO, and AHR overexpression is associated with poor outcome in diffuse large B-cell lymphoma patients in the rituximab era." Medicine 99, no. 21 (May 22, 2020): e19883. http://dx.doi.org/10.1097/md.0000000000019883.
39
Stone, Trevor W., and Richard O. Williams. "Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface." Cancers 15, no. 11 (May 24, 2023): 2895. http://dx.doi.org/10.3390/cancers15112895.
Анотація:
The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.
40
Jovanovic, Filip, Aboorva Sudhakar, and Nebojsa Nick Knezevic. "The Kynurenine Pathway and Polycystic Ovary Syndrome: Inflammation as a Common Denominator." International Journal of Tryptophan Research 15 (January 2022): 117864692210992. http://dx.doi.org/10.1177/11786469221099214.
Анотація:
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder commonly seen in females of reproductive age. The pathophysiology of PCOS is multifactorial and includes dysfunction in ovarian steroidogenesis and folliculogenesis, impaired gonadotropin levels, insulin resistance, gut microbiota imbalance, genetic predisposition, and lifestyle preferences. Low-grade inflammatory conditions such as obesity and impaired glucose tolerance are common metabolic disturbances in women with PCOS. A growing body of literature suggests strong evidence rendering PCOS in close proximity with chronic inflammation as documented by high levels of serum white blood cells, C-reactive protein, and various proinflammatory cytokines seen in this condition. Inflammation seems to be the most common metabolic denominator between the kynurenine pathway and PCOS. The association of tryptophan and kynurenine pathway has already been well documented in mood disorders, neurodegenerative diseases, chronic pain conditions, and different inflammatory states. In this manuscript, we describe the influence of sex steroid hormones on different enzymes of the KP; inflammatory nature of PCOS and CRP as a marker of IDO/TDO activity; and the effects of altered gut flora in women with PCOS. This review provides a novel view of the available evidence of tryptophan and downstream metabolites in PCOS in the context of underlying inflammation.
41
Noakes, Rowland R. "Effects of Tranilast on the Urinary Excretion of Kynurenic and Quinolinic Acid under Conditions of L Tryptophan Loading." International Journal of Tryptophan Research 6 (January 2013): IJTR.S12797. http://dx.doi.org/10.4137/ijtr.s12797.
Анотація:
The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3 di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.
42
Kubacka, Justyna, Anna Stefańska, and Grażyna Sypniewska. "Kynurenine pathway: the link between depressive disorders and inflammation." Postępy Higieny i Medycyny Doświadczalnej 74 (August 6, 2020): 331–39. http://dx.doi.org/10.5604/01.3001.0014.3454.
Анотація:
Depression is highly prevalent worldwide and the leading cause of disability. It is believed that currently more than 300 million people of all ages suffer from depression. However, the unambiguous cause of the depression remains unknown. It is suggested that the occurrence of this disease is primarily affected by genetic factors, psychological factors and atypical brain structure or function. Recently, an increasingly important role is attributed to the inflammatory response, which is considered to be the main cause of depression. Activation of the kynurenine pathway (KP) is one of the described mechanisms by which inflammation can induce depression. Kynurenine pathway activation is associated with several neuropsychiatric diseases, including major depression disorder (MDD). The imbalance between the neuroprotective and neurotoxic metabolites in the kynurenine pathway and the associated serotonin and melatonin deficiency, may contribute to the manifestation of depressive symptoms. In this review we discuss the role of the major enzymes of the tryptophan KP: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) and the role of selected kynurenic metabolites in the depressive disorders. Particular attention was also paid to the genetic basis of depressive disorders and to the summary of current knowledge on the effectiveness of treatment and supplementation with tryptophan and 5-hydroxytryptophan in depression.
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Spector, Sydney, Chunjing Wu, Dan Nguyen, George Theodore, Ashley Garcia, Lynn Feun, Niramol Savaraj, and Medhi Wangpaichitr. "Abstract 2325: Targeting kynurenine pathway using novel IDO/TDO dual inhibitor (AT0174) to modulate tumor microenvironment in platinum resistant non-small cell lung cancer cancer: An immunometabolism compliment markers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2325. http://dx.doi.org/10.1158/1538-7445.am2022-2325.
Анотація:
Abstract We discovered a crucial change common to all platinum resistant (CR) NSCLC cells, wherein a high level of reactive oxygen species (ROS) modulates tumor metabolism. CR cells activate the kynurenine (KYN) pathway (KP) during excessive oxidative stress to maintain high ROS for proliferation by catabolizing tryptophan (TRP) to KYN via indoleamine 2,3-dioxygenase-1 (IDO1); and by expressing (3-5x) higher levels of programmed death-ligand 1 (PD-L1) compared to platinum sensitive cells (p<0.02; n=8). We detected significant increases in IDO1 activity (3-4x), identified by the KYN/TRP ratio, in CR cells’ culture media (p<0.05; n=8). Extracellular KYN is known to program naïve T-cells to the immune suppressive regulatory T-cell (T-reg) phenotype. Using a human peripheral blood mononuclear cell (PBMC) co-culture system, we found a higher frequency of regulatory T-cells (Tregs; CD4+CD25+Foxp3+) and a lower frequency of effector T-cells (Teffs CD3+CD8+) and NK cell (CD3-CD314+CD335+) activity in co-culture with CR cells compared to cisplatin sensitive cancer cells. Importantly, inhibition of IDO1 and Tryptophan 2,3-Dioxygenase (TDO2), the enzymes involved in the rate limiting step in the KP, with the dual inhibitor AT-0174 at 20µM (48h) suppressed Tregs, but enhanced Teffs and NK cell populations in CR co-cultures. Next, we used a syngeneic mouse model of LLC (Lewis lung cancer) vs cisplatin resistant LLC-CR, to examine the effects of AT-0174 (170 mg/kg; P.O. once daily) in combination with anti-PD1 antibody (10 mg/ml; I.P. once every 3 days). Consistent with the in vitro model, analysis of mice with LLC-CR tumors found higher intratumoral T-reg and lower NK cell populations. Treatment with AT-0174 resulted in higher tumor infiltrating lymphocytes of Teffs and NK and lower Treg frequency in LLC-CR tumors than treatment with a selective IDO1 inhibitor (epacadostat). More importantly, the combination of AT-0174+antiPD1 reversed the immunosuppressive tumor microenvironments with further enhancement in Teffs and NK frequencies and diminished tumor growth in CR allografts with a significant reduction of total tumor weight compared with LLC mouse tumors (n=10, P<0.01). Our new findings support the potential therapeutic efficacy of the dual IDO/TDO inhibitor AT-0174 as an immuno-therapeutic treatment that enhances tumor immune surveillance and blocks tumor metabolism related survival mechanisms in platinum resistant NSCLC tumors. Support by the Dept. of Veterans Affairs. Citation Format: Sydney Spector, Chunjing Wu, Dan Nguyen, George Theodore, Ashley Garcia, Lynn Feun, Niramol Savaraj, Medhi Wangpaichitr. Targeting kynurenine pathway using novel IDO/TDO dual inhibitor (AT0174) to modulate tumor microenvironment in platinum resistant non-small cell lung cancer cancer: An immunometabolism compliment markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2325.
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Pal, Anasua, Philipp Zimmer, Dorothea Clauss, Martina E. Schmidt, Cornelia M. Ulrich, Joachim Wiskemann, and Karen Steindorf. "Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients." International Journal of Sports Medicine 42, no. 01 (July 24, 2020): 33–40. http://dx.doi.org/10.1055/a-1186-1009.
Анотація:
AbstractThe aim of this study was to investigate the impact of Supervised and Home-based resistance exercise on the Kynurenine pathway in patients with pancreatic cancer who underwent surgery and chemotherapy. In the SUPPORT study, adult pancreatic cancer patients were randomized to intervention programs of 6-month (1) a Supervised moderate-to-high-intensity progressive resistance training or (2) unsupervised Home-based resistance training, or (3) to a standard care patient Control group. Serum levels of kynurenine, tryptophan and IL-6 were assessed for 32 participants before, after 3 months and after 6 months of exercise intervention. Group differences were investigated using analysis-of-covariance. Patients in the Supervised training group showed decreased levels of serum kynurenine and kynurenine/tryptophan ratio (p = 0.07; p = 0.01 respectively) as well as increased Tryptophan levels (p = 0.05) in comparison to Home-based and Control group over time. The Home-based exercise group had significant increased kynurenine and kynurenine/tryptophan ratio levels. IL-6 levels decreased over the first three months for both intervention groups as well as the Control group (Supervised: p < 0.01, Home-based: p < 0.010, Control group: p < 0.01). Supervised resistance exercise might positively regulate the Kynurenine pathway and downregulate the kynurenine/tryptophan (indicative of IDO/TDO enzyme) levels, hence modulating the immune system.
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Giannakis, Marios, Haoxin Li, Chelsea Jin, Shuba Gopal, Kaushal Desai, Christine Horak, Megan Wind-Rotolo, et al. "Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 3036. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.3036.
Анотація:
3036 Background: Immune-checkpoint inhibition has been shown to be effective in a variety of cancers, including renal cell carcinoma (RCC) and melanoma. However, only a subset of patients with RCC and melanoma respond to anti-PD1 therapy. Given the importance of metabolism in the tumor immune microenvironment, we performed serum metabolomics in nivolumab-treated patients towards identifying novel non-invasive correlates of response and progression-free survival in immunotherapy-treated patients. Methods: We performed liquid chromatography-mass spectrometry on pre- and on-treatment serum samples from 79 patients with advanced melanoma (CA209-038 study) and 82 patients with metastatic RCC (CA209-009 study) receiving nivolumab. We precisely measured more than one-hundred named metabolites at baseline (prior to starting nivolumab), at 4 weeks and at 6 (melanoma) or 9 weeks (RCC) after initiation of treatment and correlated these with best overall response as well as progression-free survival (PFS). Results: In melanoma patients treated with nivolumab, the difference in mean levels of kynurenine (the product of IDO / TDO activity in tryptophan catabolism) between weeks 4 and 6 compared to baseline was significantly different between responders and non-responders (t-test with unequal variance p-value = 0.043 and p-value = 0.044 respectively). In RCC patients, we observed that patients with no response to nivolumab had significantly higher adenosine levels, than those who responded, at baseline and at 4 weeks after initiation of treatment (158% and 138% higher, t-test p-value = 0.0019 and p-value = 0.0011 respectively). RCC nivolumab-treated patients with higher (top quartile) baseline adenosine levels also had a significantly worse PFS (log rank test p-value = 0.004). Conclusions: In this first-of-its kind metabolomic analysis of peripheral blood from nivolumab-treated patients, we find that the change in kynurenine levels in melanoma patients correlates to response. In addition, higher baseline levels of adenosine in RCC patients are associated with worse PFS and lack of response to nivolumab. These results suggest a possible role for serum metabolites as biomarkers of benefit to PD1 inhibition.
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Pires, Ananda Staats, Shabarni Gupta, Sean A. Barton, Roshana Vander Wall, Vanessa Tan, Benjamin Heng, Jacqueline K. Phillips, and Gilles J. Guillemin. "Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease." International Journal of Tryptophan Research 15 (January 2022): 117864692211260. http://dx.doi.org/10.1177/11786469221126063.
Анотація:
Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls ( P ⩽ .05). LPK kidneys also showed an age effect ( P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls ( P ⩽ .05). Plasma XA and 3-HK also showed an age effect ( P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect ( P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.
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Papadopoulos, Kyriakos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, et al. "Abstract CT276: Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT276. http://dx.doi.org/10.1158/1538-7445.am2023-ct276.
Анотація:
Abstract Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT276.
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Dawood, Shazia, Samina Bano, and Abdulla Abu-Bakr Badawy. "Inflammation and serotonin deficiency in major depressive disorder: Molecular docking of antidepressant and antiinflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases." Bioscience Reports, May 4, 2022. http://dx.doi.org/10.1042/bsr20220426.
Анотація:
The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO), but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme, but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with antiinflammatory properties are unlikely to act by direct inhibition of IDO, but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of 6 antiinflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other 5 dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD. TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal antiinflammatory drugs. The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.
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Gualdoni, Gisela S., Patricia V. Jacobo, Cristian M. Sobarzo, Cecilia V. Pérez, María E. Matzkin, Christian Höcht, Mónica B. Frungieri, et al. "Role of indoleamine 2,3-dioxygenase in testicular immune-privilege." Scientific Reports 9, no. 1 (November 4, 2019). http://dx.doi.org/10.1038/s41598-019-52192-8.
Анотація:
Abstract Male meiotic germ cell including the spermatozoa represent a great challenge to the immune system, as they appear long after the establishment of normal immune tolerance mechanisms. The capacity of the testes to tolerate autoantigenic germ cells as well as survival of allogeneic organ engrafted in the testicular interstitium have led to consider the testis an immunologically privileged site. Disruption of this immune privilege following trauma, tumor, or autoimmune orchitis often results in male infertility. Strong evidence indicates that indoleamine 2,3-dioxygenase (IDO) has been implicated in fetal and allograft tolerance, tumor immune resistance, and regulation of autoimmune diseases. IDO and tryptophan 2,3-dioxygenase (TDO) catalyze the same rate-limiting step of tryptophan metabolism along a common pathway, which leads to tryptophan starvation and generation of catabolites collectively known as kynurenines. However, the relevance of tryptophan metabolism in testis pathophysiology has not yet been explored. Here we assessed the in vivo role of IDO/TDO in experimental autoimmune orchitis (EAO), a model of autoimmune testicular inflammation and immunologically impaired spermatogenesis. EAO was induced in adult Wistar rats with testicular homogenate and adjuvants. Control (C) rats injected with saline and adjuvants and normal untreated rats (N) were also studied. mRNA expression of IDO decreased in whole testes and in isolated Sertoli cells during EAO. TDO and IDO localization and level of expression in the testis were analyzed by immunostaining and Western blot. TDO is expressed in granulomas from EAO rats, and similar protein levels were observed in N, C, and EAO groups. IDO was detected in mononuclear and endothelial cells and reduced IDO expression was detected in EAO group compared to N and C rats. This phenomenon was concomitant with a significant reduction of IDO activity in EAO testis measured by tryptophan and kynurenine concentrations (HPLC). Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increased severity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immune regulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicular immune privilege.
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Oxenkrug, Gregory, and Valeriya Navrotska. "Extension of life span by down-regulation of enzymes catalyzing tryptophan conversion into kynurenine: Possible implications for mechanisms of aging." Experimental Biology and Medicine, June 10, 2023, 153537022311794. http://dx.doi.org/10.1177/15353702231179411.
Анотація:
The end products of catabolism of tryptophan (Trp), an essential amino acid, are known to affect mechanism(s) of aging, a neurodegenerative condition. This review focuses on the possible role of the initial step of Trp catabolism, kynurenine (Kyn) formation from Trp, in aging mechanism(s). Rate-limiting enzymes of Trp conversion into Kyn are tryptophan 2,3-dioxygenase 2 (TDO) or indoleamine 2,3-dioxygenase (IDO). Aging is associated with up-regulated production of cortisol, an activator of TDO, and pro-inflammatory cytokines, inducers of IDO. The other rate-limiting enzyme of Kyn formation from Trp is ATP-binding cassette (ABC) transporter that regulates Trp availability as a substrate for TDO. Inhibitors of TDO (alpha-methyl tryptophan) and ABC transporter (5-methyltryptophan) extended life span of wild-type Drosophila. Life span prolongation was observed in TDO knockdown of Caenorhabditis elegans and in TDO or ABC transporter–deficient Drosophila mutants. Down-regulation of enzymes catalyzing Kyn conversion into kynurenic acid (KYNA) and 3-hydroxykynurenine decreases life span. Considering that down-regulation of Methuselah (MTH) gene prolonged life span, aging-accelerating effect of KYNA, a GPR35/MTH agonist, might depend on MTH gene activation. Mice treated with TDO inhibitor, benserazide, an ingredient of anti-Parkinson medication carbidopa, and TDO-deficient Drosophila mutants were resistant to inducement of aging-associated Metabolic Syndrome by high-sugar or high-fat diets. Up-regulation of Kyn formation was associated with accelerated aging and increased mortality in human subjects. Trp–Kyn pathway is evolutionary conserved (from yeasts, through insects, worms, vertebrates to humans). Further studies might explore possible antiaging effect of down-regulation of Kyn formation from Trp by dietary, pharmacological, and genetic interventions.