Turn Off the IDO: Will Clinical Trials Be Successful?

Novitskiy, Sergey V.; Moses, Harold L.

doi:10.1158/2159-8290.cd-12-0311

Cited by 11 publications

(13 citation statements)

References 12 publications

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“…High expressions of IDO are observed in patients with hepatocellular carcinoma, non‐small cell lung cancer, colon cancer and invasive cervical carcinoma, leading to poor prognosis . IDO could be expressed by tumor cells and plasmacytoid dendritic cells (pDCs), thus it localizes both in TMEs and TDLNs . In tumor‐bearing animal models, the tumor‐induced IDO helps to create a tolerogenic immune circumstance within TME and associated TDLNs .…”

mentioning

confidence: 99%

“…16 IDO could be expressed by tumor cells and plasmacytoid dendritic cells (pDCs), thus it localizes both in TMEs and TDLNs. 17 In tumor-bearing animal models, the tumor-induced IDO helps to create a tolerogenic immune circumstance within TME and associated TDLNs. 18 At the same time, IDO could cooperate with Tregs to upregulate the expression of vascular endothelium growth factor-A (VEGF-A) to promote lymphoangiogenesis for building pathways of metastasis.…”

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confidence: 99%

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Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Jia

Wang

et al. 2015

Intl Journal of Cancer

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Indoleamine 2,3-dioxygenase (IDO) has been reported to be involved in esophageal squamous cell cancer (ESCC) progression by promoting immune escape. Previous studies have revealed bridging integrator-1 (Bin1) can inhibit cancer cell growth by suppressing expression of IDO, thus we investigated the correlation between the expression of Bin1 and IDO and their prognostic significances for ESCC patients. Specimens were collected from 196 ESCC patients and detected with flow cytometry, reverse transcription-polymerase chain reaction and immunohistochemistry. We found that in tumor microenvironment (TME) and tumor draining lymph node (TDLN), the proportions of CD3(+) CD4(+) T cell, CD3(+) CD8(+) T cell and CD3(-) CD16(+) CD56(+) NK cell were lower while the proportions of CD3(-) CD19(+) B cell and CD4(+) CD25(+) Treg were higher in specimens with high IDO expression when compared to the specimens with low IDO expression (p < 0.01). In addition, IDO expression was negatively correlated with Bin1 expression at gene and protein level in TME and TDLN. Both the expression of Bin1 and IDO were associated with some clinicopathological parameters including differentiation grade, TNM stage, invasion range, lymph node metastasis (p < 0.05). Moreover, multivariate survival analysis suggested that, along with some other parameters, low expression of Bin1 and high expression of IDO might be independent prognostic factor for ESCC patients. Our results demonstrate that low expression of Bin1, along with high expression of IDO, are predictor for poor prognosis in ESCC and thereby could be used to establish new therapeutic strategies.

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confidence: 99%

mentioning

confidence: 99%

Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Jia

Wang

et al. 2015

Intl Journal of Cancer

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“…Also, sodium butyrate has been described to inhibit STAT1 signaling and to upregulate IDO ubiquitination in human nasopharyngeal cancer cell lines [36]. While the main strategy currently envisioned to tackle IDO clinically is by inhibiting its enzymatic activity [37], our study demonstrates that IDO is sensitive to proteasomal degradation, which can be enhanced with fludarabine. Enhancing IDO degradation is an interesting alternative and a complementary approach to the enzymatic inhibition of IDO.…”

Section: Discussionmentioning

confidence: 68%

Fludarabine Downregulates Indoleamine 2,3-Dioxygenase in Tumors via a Proteasome-Mediated Degradation Mechanism

et al. 2014

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Indoleamine 2,3-dioxygenase (IDO) is found in multiple malignancies and exerts immunosuppressive effects that are central in protecting tumors from host T lymphocyte rejection. IDO is an enzyme involved in the catabolism of tryptophan resulting in inhibition of T lymphocyte function. While inhibition of IDO enzymatic activity results in tumor rejection, it is still unknown how we can directly target IDO expression within tumors using drugs. We have chosen to interfere with IDO expression by targeting the key-signaling event signal transducer and activator of transcription 1 (STAT1). We evaluated the efficacy of fludarabine, previously described to inhibit STAT1 phosphorylation. Interestingly, fludarabine was efficient in suppressing protein expression and consequently IDO activity in two different cell lines derived from breast cancer and melanoma when IDO was activated with interferon-gamma (IFN-γ) or supernatants prepared from activated T lymphocytes. However, fludarabine had no inhibitory effect on STAT1 phosphorylation. Other IFN-γ-responsive genes were only marginally inhibited by fludarabine. The level of IDO transcript was unaffected by this inhibitor, suggesting the involvement of post-transcriptional control. Strikingly, we have found that the inhibition of proteasome partially protected IDO from fludarabine-induced degradation, indicating that fludarabine induces IDO degradation through a proteasome-dependent pathway. Currently used in the clinic to treat some malignancies, fludarabine has the potential for use in the treatment of human tumors through induction of IDO degradation and consequently, for the promotion of T cell-mediated anti-tumor response.

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“…This information is vital for understanding enzyme-substrate interactions in h IDO1 and for designing inhibitors with enhanced therapeutic responses. 29,30,31 Using a new assay methodology, we quantify the effects of O 2 concentration on the initial rates of h IDO1 catalysis. We analyze the data within a mechanistic model that allows for initial complexation of either O 2 or L-Trp with a free ferrous form of h IDO1 – Fe(II) h IDO1.…”

Section: Introductionmentioning

confidence: 99%

Catalytic activity of human indoleamine 2,3-dioxygenase (hIDO1) at low oxygen

Kolawole

Hixon

Dameron

et al. 2015

Archives of Biochemistry and Biophysics

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A cytokine-inducible extrahepatic human indoleamine 2,3-dioxygenase (hIDO1) catalyzes the first step of the kynurenine pathway. Immunosuppressive activity of hIDO1 in tumor cells weakens host T-cell immunity, contributing to the progression of cancer. Here we report on enzyme kinetics and catalytic mechanism of hIDO1, studied at varied levels of dioxygen (O2) and L-tryptophan (L-Trp). Using a cytochrome b5-based activating system, we measured the initial rates of O2 decay with a Clark-type oxygen electrode at physiologically-relevant levels of both substrates. Kinetics was also studied in the presence of two substrate analogs: 1-methyl-L-tryptophan and norharmane. Quantitative analysis supports a steady-state rather than a rapid equilibrium kinetic mechanism, where the rates of individual pathways, leading to a ternary complex, are significantly different, and the overall rate of catalysis depends on contributions of both routes. One path, where O2 binds to ferrous hIDO1 first, is faster than the second route, which starts with the binding of L-Trp. However, L-Trp complexation with free ferrous hIDO1 is more rapid than that of O2. As the level of L-Trp increases, the slower route becomes a significant contributor to the overall rate, resulting in observed substrate inhibition.

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Turn Off the IDO: Will Clinical Trials Be Successful?

Cited by 11 publications

References 12 publications

Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients

Fludarabine Downregulates Indoleamine 2,3-Dioxygenase in Tumors via a Proteasome-Mediated Degradation Mechanism

Catalytic activity of human indoleamine 2,3-dioxygenase (hIDO1) at low oxygen

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