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https://www.readbyqxmd.com/read/28731684/the-binding-mode-of-n-hydroxyamidines-to-indoleamine-2-3-dioxygenase-1-ido1
#1
Ute Friederike Röhrig, Vincent Zoete, Olivier Michielin
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through a N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or nitrogen atoms. Here, we use quantum chemical calculations, docking, and QM/MM calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode...
July 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28726189/changing-the-properties-of-multipotent-mesenchymal-stromal-cells-by-ifn%C3%AE-administration
#2
N A Petinati, N M Kapranov, A E Bigil'deev, M D Popova, Yu O Davydova, I V Gal'tseva, N I Drize, L A Kuz'mina, E N Parovichnikova, V G Savchenko
We studied changes in the population of human multipotent mesenchymal stromal cells activated by IFNγ. The cells were cultured under standard conditions; IFNγ was added in various concentrations for 4 h or over 2 passages. It was shown that the total cell production significantly decreased after long-term culturing with IFNγ, but 4-h exposure did not affect this parameter. After 4-h culturing, the expression levels of IDO1, CSF1, and IL-6 increased by 300, 7, and 2.4 times, respectively, and this increase persisted 1 and 2 days after removal of IFNγ from the culture medium...
July 19, 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28701757/oncolytic-measles-virus-enhances-antitumour-responses-of-adoptive-cd8-nkg2d-cells-in-hepatocellular-carcinoma-treatment
#3
Aiping Chen, Yonghui Zhang, Gang Meng, Dengxu Jiang, Hailin Zhang, Meihong Zheng, Mao Xia, Aiqin Jiang, Junhua Wu, Christian Beltinger, Jiwu Wei
There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8(+)NKG2D(+) cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8(+)NKG2D(+) cells, mediated by at least three distinct mechanisms...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698009/a-randomised-open-label-phase-2-study-of-the-ido1-inhibitor-epacadostat-incb024360-versus-tamoxifen-as-therapy-for-biochemically-recurrent-ca-125-relapse-only-epithelial-ovarian-cancer-primary-peritoneal-carcinoma-or-fallopian-tube-cancer
#4
Rebecca Kristeleit, Irina Davidenko, Vadim Shirinkin, Fatima El-Khouly, Igor Bondarenko, Michael J Goodheart, Vera Gorbunova, Carol A Penning, Jack G Shi, Xiangdong Liu, Robert C Newton, Yufan Zhao, Janet Maleski, Lance Leopold, Russell J Schilder
OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months)...
July 8, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28697066/viral-induced-modulation-of-multiple-checkpoint-proteins-in-cancers
#5
Gerard J Nuovo, Virginia A Folcik, Cynthia Magro
Therapy with checkpoint inhibitors represents a major advance in cancer treatment. The purpose of this study was to examine the expression patterns of the checkpoint proteins programmed death ligand 1 (PD L1), PD L2, indoleamine 2,3-dioxygenase 1 (IDO1), and cytotoxic T-lymphocyte antigen 4 (CTLA4) in cancers including those associated with viral infections. Normal, noninflamed tissues rarely express checkpoint proteins with exceptions including the placenta and stomach. Expression of PD L1 was noted in 30%, PD L2 in 18%, IDO1 in 13%, and CTLA4 in 14% of 333 nonviral malignancies including endometrial, ovarian, lung, and breast cancers...
July 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28689792/functional-role-of-kynurenine-and-aryl-hydrocarbon-receptor-axis-in-chronic-rhinosinusitis-with-nasal-polyps
#6
Heng Wang, Danh C Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E Anderson, Zheng Liu, Peisong Gao
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: Determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured expression of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls...
July 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28687008/association-of-breast-carcinoma-growth-with-a-non-canonical-axis-of-ifn%C3%AE-ido1-tsp1
#7
Bruno Lopes-Bastos, Liang Jin, Fiona Ruge, Sioned Owen, Andrew Sanders, Christopher Cogle, John Chester, Wen G Jiang, Jun Cai
Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28667875/discovery-of-potent-ido1-inhibitors-derived-from-tryptophan-using-scaffold-hopping-and-structure-based-design-approaches
#8
Yi Zou, Yan Wang, Fang Wang, Minghao Luo, Yuezhen Li, Wen Liu, Zhangjian Huang, Yihua Zhang, Wenjie Guo, Qiang Xu, Yisheng Lai
Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28662235/use-of-pd-1-targeting-macrophage-infiltration-and-ido-pathway-activation-in-sarcomas-a-phase-2-clinical-trial
#9
Maud Toulmonde, Nicolas Penel, Julien Adam, Christine Chevreau, Jean-Yves Blay, Axel Le Cesne, Emmanuelle Bompas, Sophie Piperno-Neumann, Sophie Cousin, Thomas Grellety, Thomas Ryckewaert, Alban Bessede, François Ghiringhelli, Marina Pulido, Antoine Italiano
Importance: There is a strong rationale for treating sarcomas with immunotherapy. Objective: To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants: This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST)...
June 29, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28659861/the-effect-of-systemic-nitroglycerin-administration-on-the-kynurenine-pathway-in-the-rat
#10
Gábor Nagy-Grócz, Klaudia F Laborc, Gábor Veres, Attila Bajtai, Zsuzsanna Bohár, Dénes Zádori, Annamária Fejes-Szabó, Eleonóra Spekker, László Vécsei, Árpád Párdutz
The primary headache disorders include migraine, which is one of the most frequent neurological disorders, which influences more than 14% of the whole population. Despite the research efforts, its exact pathomechanism is not fully revealed, but evidence points to the role of glutamate and its receptors. Kynurenic acid is an endogenous glutamate receptor antagonist produced by the kynurenine pathway (KP). Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) convert l-tryptophan to N-formyl-l-kynurenine, to be further transformed to l-kynurenine...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28650043/heme-containing-enzymes-and-inhibitors-for-tryptophan-metabolism
#11
REVIEW
Daojing Yan, Ying-Wu Lin, Xiangshi Tan
Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and the accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies...
June 26, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28639129/the-inhibition-of-indoleamine-2-3-dioxygenase-accelerates-early-liver-regeneration-in-mice-after-partial-hepatectomy
#12
Hideyuki Ogiso, Hiroyasu Ito, Ayumu Kanbe, Tatsuya Ando, Akira Hara, Masahito Shimizu, Hisataka Moriwaki, Mitsuru Seishima
BACKGROUND AND AIM: The inflammatory response accelerates early liver regeneration after liver injury and resection. Recent studies have demonstrated that indoleamine 2,3-dioxygenase-1 (IDO1) suppresses the activation of inflammatory cells and induces immune tolerance. In this study, we examined the role of IDO1 in liver regeneration after partial hepatectomy (PHx). METHODS: WT or IDO1-knockout (IDO1-KO) mice received 70% PHx. The liver-body weight ratio after PHx was measured and hepatocyte growth was assessed by immunostaining...
June 21, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28632999/long-noncoding-rna-lnc-sox5-modulates-crc-tumorigenesis-by-unbalancing-tumor-microenvironment
#13
Kaiming Wu, Zhenxian Zhao, Kuanzhi Liu, Jian Zhang, Guanghua Li, Liang Wang
Long non-coding RNAs (LncRNAs) have been recently regarded as systemic regulators in multiple biologic processes including tumorigenesis. In this study, we observed the expression of lncRNA lnc-sox5 was significantly increased in colorectal cancer (CRC). Despite the CRC cell growth, cell cycle and cell apoptosis was not affected by lnc-sox5 knock-down, lnc-sox5 knock-down suppressed CRC cell migration and invasion. In addition, xenograft animal model suggested that lnc-sox5 knock-down significantly suppressed the CRC tumorigenesis...
June 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28625979/intestine-specific-homeobox-gene-isx-integrates-interleukin-6-signaling-tryptophan-catabolism-and-immune-suppression
#14
Li-Ting Wang, Shyh-Shin Chiou, Chee-Yin Chai, Edward Hsi, Kazunari K Yokoyama, Shen-Nien Wang, Shau-Ku Huang, Shih-Hsien Hsu
The intestine-specific homeobox transcription factor ISX is an IL-6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma (HCC), but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan cataboism and immune suppression. We found that ISX mediated IL-6-induced expression of the tryptophan catabolic enzymes IDO1 and TDO2 in HCC cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR)...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28588282/comparison-and-immunobiological-characterization-of-retinoic-acid-inducible-gene-i-like-receptor-expression-in-mesenchymal-stromal-cells
#15
Gordana Raicevic, Mehdi Najar, Hélène Busser, Emerence Crompot, Dominique Bron, Michel Toungouz, Laurence Lagneaux
Due to their immunomodulatory and regenerative properties, Mesenchymal stromal cells (MSC) have generated major interests in several clinical settings including transplantation and inflammatory diseases. MSC functions can be influenced by their tissue origin. Their microenvironment strongly affects their biology notably through TLR sensing. In this study, we show that MSC isolated from four different sources express another type of cytosolic pathogen recognition receptors known as retinoic acid inducible gene-I (RIG-I)-like receptors (RLR)...
June 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28557618/microenvironment-tumor-metabolic-interactions-highlighted-by-qmsi-application-to-the-tryptophan-kynurenine-pathway-in-immuno-oncology
#16
Rima Ait-Belkacem, Vanesa Bol, Gregory Hamm, Florence Schramme, Benoit Van Den Eynde, Lauranne Poncelet, Fabien Pamelard, Jonathan Stauber, Bruno Gomes
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
May 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28546465/quantitative-mass-spectrometry-analysis-of-pd-l1-protein-expression-n-glycosylation-and-expression-stoichiometry-with-pd-1-and-pd-l2-in-human-melanoma
#17
Carlos A Morales-Betanzos, Hyoungjoo Lee, Paula I Gonzalez-Ericsson, Justin M Balko, Douglas B Johnson, Lisa J Zimmerman, Daniel C Liebler
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody...
May 25, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28545736/amino-acid-sensing-and-degrading-pathways-in-immune-regulation
#18
Ursula Grohmann, Giada Mondanelli, Maria L Belladonna, Ciriana Orabona, Maria T Pallotta, Alberta Iacono, Paolo Puccetti, Claudia Volpi
Indoleamine 2,3-dioxygenases (IDOs) - belonging in the heme dioxygenase family and degrading tryptophan - are responsible for the de novo synthesis of nicotinamide adenine dinucleotide (NAD(+)). As such, they are expressed by a variety of invertebrate and vertebrate species. In mammals, IDO1 has remarkably evolved to expand its functions, so to become a prominent homeostatic regulator, capable of modulating infection and immunity in multiple ways, including local tryptophan deprivation, production of biologically active tryptophan catabolites, and non-enzymatic cell-signaling activity...
May 18, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28541512/the-interplay-between-metabolic-remodeling-and-immune-regulation-in-glioblastoma
#19
Pravin Kesarwani, Shiva Kant, Antony Prabhu, Prakash Chinnaiyan
The fields of tumor metabolism and immune oncology have both independently received considerable attention over the last several years. The majority of research in tumor metabolism has largely focused on the Warburg effect and its resulting biologic consequences, including energy and macromolecule production. However, recent investigations have identified elegant, multifaceted strategies by which alterations in tumor metabolism can also contribute towards a potent tolerogenic immune environment. One of the most notable is increased tryptophan metabolism through activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) pathways...
May 25, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28537889/immune-signature-of-metastatic-breast-cancer-identifying-predictive-markers-of-immunotherapy-response
#20
Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park
In breast cancer (BC), up to 10-20% patients were known to have clinical benefit with immune checkpoint inhibitors, and biomarkers are needed for optimal use of this multi-potential therapeutic strategy. Accordingly, we conducted an experiment to identify expression of genes associated with immune checkpoints that represent potential targets of cancer immunotherapy. We performed whole-transcriptome sequencing and whole-exome sequencing using 37 refractory BC specimens. In the immune pathway gene set expression analysis, we found that HER2 expression and previous taxane treatment were positively correlated with high expression of immune gene set expression (p = 0...
May 7, 2017: Oncotarget
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