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ido 1 inhibitor

Xuan-Tong Liu, Hui-Ting Sun, Zhong-Fang Zhang, Ru-Xia Shi, Li-Bing Liu, Jia-Jun Yu, Wen-Jie Zhou, Chun-Jie Gu, Shao-Liang Yang, Yu-Kai Liu, Hui-Li Yang, Feng-Xuan Xu, Ming-Qing Li
It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK...
August 7, 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Massimiliano Salati, Annalinda Pisano, Mazzuca Federica, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti
BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment...
August 6, 2018: Journal of Translational Medicine
Miwa Fukuda, Tomomi Sasaki, Tomoko Hashimoto, Hiroyuki Miyachi, Minoru Waki, Akira Asai, Osamu Takikawa, Osamu Ohno, Kenji Matsuno
Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production. Further derivatisation of 2b-6 provided the potent inhibitor of cellular kynurenine production 2i (IC50  = 0...
July 20, 2018: Bioorganic & Medicinal Chemistry Letters
Tali Ofir Dovrat, Ethan Sokol, Garrett Frampton, Eliya Shachar, Sharon Pelles, Ravit Geva, Ido Wolf
INTRODUCTION: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies. Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation...
July 23, 2018: Cancer Biology & Therapy
Qiang Luo, Liang Yan, Pan Xu, Chuan Xiong, Zhirong Yang, Peng Hu, Huidong Hu, Ren Hong
The present study examined the role of a polysaccharide (LSP, 25 and 100 μg/ml) from the fruiting bodies of Lepista sordid on the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells, and the possible mechanism of action. IDO expression and kynurenine production from LSP-treated HepG2 cells following IFN-γ stimulation were dramatically inhibited by LSP treatment. In line with this, the medium of HepG2 cells pretreated with LSP improved the survival rate of primary CD4+ and CD8+ T cells as compared with IFN-γ-treated control cells...
October 1, 2018: Carbohydrate Polymers
Dagmar Hildebrand, Mariel-Esther Eberle, Sabine Marie Wölfle, Franziska Egler, Delal Sahin, Aline Sähr, Konrad A Bode, Klaus Heeg
Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3...
2018: Frontiers in Immunology
Zachary J Brown, Su Jong Yu, Bernd Heinrich, Chi Ma, Qiong Fu, Milan Sandhu, David Agdashian, Qianfei Zhang, Firouzeh Korangy, Tim F Greten
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC...
June 29, 2018: Cancer Immunology, Immunotherapy: CII
Ashley Volaric, Ryan Gentzler, Richard Hall, James H Mehaffey, Edward B Stelow, Timothy N Bullock, Linda W Martin, Anne M Mills
The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown...
June 12, 2018: American Journal of Surgical Pathology
Jinrong Peng, Yao Xiao, Wenting Li, Qian Yang, Liwei Tan, Yanpeng Jia, Ying Qu, Zhiyong Qian
The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism-related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy...
May 2018: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Julien Taieb, Markus Moehler, Narikazu Boku, Jaffer A Ajani, Eduardo Yañez Ruiz, Min-Hee Ryu, Silke Guenther, Vikram Chand, Yung-Jue Bang
BACKGROUND: Standard treatment options for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) are associated with limited efficacy and some toxicity. Recently, immunotherapy with antibodies that inhibit the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction has emerged as a new treatment option. This manuscript reviews early-phase and late-phase trials of immunotherapy in advanced GC/GEJC. METHODS: Searches for studies of immunotherapy in GC/GEJC were performed using PubMed, ClinicalTrials...
May 2018: Cancer Treatment Reviews
Lijuan Wei, Shanshan Zhu, Menghui Li, Fangxuan Li, Feng Wei, Juntian Liu, Xiubao Ren
Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy. IDO has also received more attention because of its non-immune functions including regulating angiogenesis. The purpose of this study was to investigate the effects of IDO on microvessel density (MVD), and to explore its prognostic role in breast cancer. We showed IDO expression was positively correlated with MVD labeled by CD105 (MVD-CD105) rather than MVD labeled by CD31 (MVD-CD31) in breast cancer specimens...
2018: Frontiers in Immunology
Theodoros Eleftheriadis, Georgios Pissas, Vassilios Liakopoulos, Ioannis Stefanidis
It is generally hypothesized in the literature that indoleamine 2,3‑dioxygenase (IDO), by degrading L‑tryptophan along the kynurenine pathway, suppresses CD4+ T‑cell function by inducing apoptosis, inhibiting proliferation and promoting differentiation towards a regulatory phenotype. These effects are either accompanied or directly lead to alterations in cell metabolism. The present study evaluated the pathways that govern the effect of IDO on the utilization of the three main energy sources in CD4+ T‑cells...
July 2018: International Journal of Molecular Medicine
Teresa Mena-Barragán, M Isabel García-Moreno, Alen Sevšek, Tetsuya Okazaki, Eiji Nanba, Katsumi Higaki, Nathaniel I Martin, Roland J Pieters, José M García Fernández, Carmen Ortiz Mellet
A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d- gluco or l- ido ), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′ -octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase)...
April 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Xiuting Liu, Wei Zhou, Xin Zhang, Yang Ding, Qianming Du, Rong Hu
Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells...
April 1, 2018: International Journal of Cancer. Journal International du Cancer
Theodoros Eleftheriadis, Georgios Pissas, Vassilios Liakopoulos, Ioannis Stefanidis
Indoleamine 2, 3-dioxygenase (IDO) suppresses T-cell function at least in part by altering cell metabolism. Hypoxia-inducible factor-1 (HIF-1) increases upon T-cell activation and alters cell metabolism favoring their differentiation to effector cells. The effect of IDO on HIF-1α expression and activity was evaluated. For this purpose, mixed lymphocyte reaction (MLR) was performed using the IDO inhibitor 1-DL-methyl-tryptophan and the p53 inhibitor pifithrin-α. L-tryptophan degradation and cell proliferation were assessed by enzyme-linked immunosorbent assay, whereas the expression of proteins of interest by western blotting...
February 2018: Iranian Journal of Allergy, Asthma, and Immunology
Laurence Booth, Jane L Roberts, Rumeesa Rais, John Kirkwood, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Andrew Poklepovic, Paul Dent
The irreversible ERBB1/2/4 inhibitor neratinib has been shown in vitro to rapidly reduce the expression of ERBB1/2/4 and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that neratinib and valproate interact to suppress the growth of 4T1 mammary tumors but had not defined whether the [neratinib + valproate] drug combination, in a mouse, had altered the biology of the 4T1 cells. Exposure of 4T1 mammary tumors to [neratinib + valproate] for three days resulted, two weeks later, in tumors that expressed less ERBB1, K-RAS, N-RAS, indoleamine-pyrrole 2,3-dioxygenase (IDO-1), ornithine decarboxylase (ODC) and had increased Class I MHCA expression...
January 19, 2018: Oncotarget
Nevena Gajovic, Milena Jurisevic, Jelena Pantic, Gordana Radosavljevic, Nebojsa Arsenijevic, Miodrag L Lukic, Ivan Jovanovic
Diabetic patients have higher incidence and mortality of cancer. Recent study revealed that hyperglycemia-induced oxidative stress is involved in the acceleration of tumor metastasis. We used model of high-dose streptozotocin-induced diabetes to investigate its effect on tumor growth and modulation of antitumor immune response of 4T1 murine breast cancer in BALB/c mice. Diabetes accelerated tumor appearance, growth and weight, which was associated with decreased NK cells cytotoxicity against 4T1 tumor cells in vitro Diabetes reduced frequencies of systemic NKG2D+ , perforin+ , granzyme+ , IFN-γ+ and IL-17+ NK cells, while increased level of PD-1 expression and production of IL-10 in NK cells...
April 2018: Endocrine-related Cancer
Lilla Hornyák, Nikoletta Dobos, Gábor Koncz, Zsolt Karányi, Dénes Páll, Zoltán Szabó, Gábor Halmos, Lóránt Székvölgyi
Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers...
2018: Frontiers in Immunology
Aline Bozec, Yubin Luo, Cecilia Engdahl, Camille Figueiredo, Holger Bang, Georg Schett
BACKGROUND: The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes...
February 7, 2018: Arthritis Research & Therapy
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
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