1‐L‐MT, an IDO inhibitor, prevented colitis‐associated cancer by inducing CDC20 inhibition‐mediated mitotic death of colon cancer cells

Liu, Xiuting; Zhang, Xin; Ding, Yang; Du, Qianming; Hu, Rong

doi:10.1002/ijc.31417

Cited by 46 publications

(48 citation statements)

References 45 publications

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“…Actually, our data show that BET inhibitors inhibit tumor growth and simultaneously reduce the IDO1 expression in the xenografts. However, although IDO1 and its metabolites have been reported to directly promote the cell proliferation and tumorigenesis and inhibit apoptosis in colon cancer cells 32–34 , our current data could still not establish a direct causal link between the tumor regression and the reduced IDO1 expression following the treatment with BET inhibitors, which requires additional investigations. Nevertheless, those consistent in vitro and in vivo data suggest that the reduction of the IDO1 expression responding to the treatment of BET inhibitors might be used as a pharmacodynamic marker to monitor the pharmacological effects of BET inhibitors on IDO1-expressing tumors.…”

Section: Discussioncontrasting

confidence: 63%

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Tian

Chen

et al. 2019

Cell Death Dis

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The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l -kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1 . Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l -kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l -kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.

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Section: Discussioncontrasting

confidence: 63%

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Tian

Chen

et al. 2019

Cell Death Dis

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“…Both MAD2L1 and CDC20 were more highly expressed in higher grade tumors than in low-grade tumors. High MAD2L1 or CDC20 levels may allow for the development of multi-organ aggressive tumors, including those affecting the breasts, lungs, liver, and stomach [ 23 – 25 ]. Collectively, these findings suggest that MAD2L1 and CDC20 may be key regulators of tumor severity, ultimately dictating patient survival.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation biomarkers for hepatocellular carcinoma

Fan

Cai

et al. 2018

Cancer Cell Int

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BackgroundAberrant methylation of DNA is a key driver of hepatocellular carcinoma (HCC). In this study, we sought to integrate four cohorts profile datasets to identify such abnormally methylated genes and pathways associated with HCC.MethodsTo this end, we downloaded microarray datasets examining gene expression (GSE84402, GSE46408) and gene methylation (GSE73003, GSE57956) from the GEO database. Abnormally methylated differentially expressed genes (DEGs) were sorted and pathways were analyzed. The String database was then used to perform enrichment and functional analysis of identified pathways and genes. Cytoscape software was used to create a protein–protein interaction network, and MCODE was used for module analysis. Finally, overall survival analysis of hub genes was performed by the OncoLnc online tool.ResultsIn total, we identified 19 hypomethylated highly expressed genes and 14 hypermethylated lowly expressed genes at the screening step, and finally found six mostly changed hub genes including MAD2L1, CDC20, CCNB1, CCND1, AR and ESR1. Pathway analysis showed that aberrantly methylated-DEGs mainly associated with the cell cycle process, p53 signaling, and MAPK signaling in HCC. After validation in TCGA database, the methylation and expression status of hub genes was significantly altered and same with our results. Patients with high expression of MAD2L1, CDC20 and CCNB1 and low expression of CCND1, AR, and ESR1 was associated with shorter overall survival.ConclusionsTaken together, we have identified novel aberrantly methylated genes and pathways linked to HCC, potentially offering novel insights into the molecular mechanisms governing HCC progression and serving as novel biomarkers for precision diagnosis and disease treatment.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0629-5) contains supplementary material, which is available to authorized users.

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“…Liu et al78 reported that 1-L-MT, an inhibitor of IDO, can be used to prevent and treat cancer because of its ability to suppress cancer cell proliferation via inhibiting mitosis. It decreases CDC20 transcription to cause G2/M cycle arrest and facilitates mitochondrial injuries as well as cancer cell apoptosis.…”

Section: The Inhibitors Of Ido or Tdo In Treatmentmentioning

confidence: 99%

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

Ye¹,

Yue²,

Shi³

et al. 2019

J. Cancer

143

111

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Kynurenine (Kyn) pathway is a significant metabolic pathway of tryptophan (Trp). The metabolites of the Kyn pathway are closely correlated with numerous diseases. Two main enzymes, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO or TDO2), regulate the first and rate-limiting step of the Kyn pathway. These enzymes are directly or indirectly involved in various diseases, including inflammatory diseases, cancer, diabetes, and mental disorders. Presently, an increasing number of potential mechanisms have been revealed. In the present review, we depict the structure of IDO and TDO and explicate their functions in various diseases to facilitate a better understanding of them and to indicate new therapeutic plans to target them. Moreover, we summarize the inhibitors of IDO/TDO that are currently under development and their efficacy in the treatment of cancer and other diseases.

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1‐L‐MT, an IDO inhibitor, prevented colitis‐associated cancer by inducing CDC20 inhibition‐mediated mitotic death of colon cancer cells

Cited by 46 publications

References 45 publications

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine

DNA methylation biomarkers for hepatocellular carcinoma

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

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