Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy

Miyazaki, Takeshi; Moritake, Kouzo; Yamada, Kazuo; Hara, Nobumasa; Osago, Harumi; Shibata, Tomoko; Akiyama, Yasuhiko; Tsuchiya, Masaharu

doi:10.3171/2008.10.jns081141

Cited by 62 publications

(56 citation statements)

References 25 publications

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“…Constitutive IDO-1 expression has been shown in 9 of 10 human glioblastoma biopsies (8) and in brain tumor cell lines (50). It is also known that IDO-1 activity in human glial and malignant glioma cell lines is increased by IFN-g (50). Thus, expression of IDO-1 in brain tumor cells is likely to be triggered when IFN-g is produced from activated T cells and/or microglia and neurons.…”

Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

“…56). Constitutive IDO-1 expression has been shown in 9 of 10 human glioblastoma biopsies (8) and in brain tumor cell lines (50). It is also known that IDO-1 activity in human glial and malignant glioma cell lines is increased by IFN-g (50).…”

Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

“…Miyazaki and colleagues showed that in several cultured human malignant glioma cell lines, exposure to IFN-g significantly decreased the levels of L-tryptophan in the culture medium concomitant with greatly increased IDO-1 expression. They also showed that the IDO-1 inhibitor 1-methyl-tryptophan (1-MT) effectively prevented L-tryptophan depletion (50).…”

Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

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The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD þ ), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the T H 17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression. Cancer Res; 72(22); 5649-57. Ó2012 AACR.

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Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

Section: Initiation Of Antitumor Immune Responses: Key Mechanisms Andmentioning

confidence: 99%

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The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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“…A few studies of iDo inhibitors against GBM have been carried out and these agents do show some activity as single agents. Miyazaki et al showed the iDo inhibitor 1-methyl L-tryptophan (1MT) prevented tryptophan consumption and suppressed the growth of LN 229 glioma cells (192). Hanihara et al reported 1MT significantly suppressed tumor growth in a murine glioma model.…”

Section: Inhibitors Of the Kynurenine Pathwaymentioning

confidence: 99%

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Sordillo

Helson

2017

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“…The inhibition of IDO expression could significantly suppress tumor growth and promote the anti-tumor activities of various immunotherapeutic agents in relevant animal models (11,12). More importantly, previous studies of our group have reported that IFN-γ induces the expression of IDO via the Janus kinase/ signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway (13,14).…”

Section: Introductionmentioning

confidence: 99%

SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells

et al. 2012

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Abstract. The aim of the present study was to investigate the role of the JAK/STAT1 signaling pathway in suberoylanilide hydroxamic acid (SAHA)-mediated down-regulation of indoleamine 2,3-dioxygenase (IDO) in gallbladder carcinoma cells. We treated SGC-996 gallbladder carcinoma cells with IFN-γ and SAHA. Western blotting was used to detect the expression of IDO, signal transducer and activator of transcription 1 (STAT1) phosphorylation and interferon regulatory factor genes-1 (IRF-1). Confocal microscopy analysis was used to detect STAT1 translocation. Transient transfection and reporter gene assay was used for detecting the activation of γ-activated sites (GAS) and interferon-stimulated response elements (ISRE). The results revealed that IDO was expressed in SGC-996 cells in a dose-and time-dependent manner when stimulated with IFN-γ and SAHA down-regulated the expression of IDO induced by IFN-γ in a dose-dependent manner.SAHA blocked the expression of IRF-1 induced by IFN-γ and SAHA inhibited IFN-γ-induced STAT1 phosphorylation and nuclear translocation. In addition, SAHA down-regulated IFN-γ-induced activation of GAS and ISRE. In conclusion, SAHA down-regulated IDO expression via inhibition of the activation of members of the JAK/STAT1 signaling pathway. Therefore, regulation of the JAK/STAT1 signaling pathway may provide a new gallbladder carcinoma immunotherapeutic strategy to break tumor immune tolerance.

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Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy

Cited by 62 publications

References 25 publications

The Kynurenine Pathway in Brain Tumor Pathogenesis

The Kynurenine Pathway in Brain Tumor Pathogenesis

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells

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