ABSTRACT
Colorectal cancer (CRC) is the third most lethal cancer and leading cause of cancer mortality worldwide. A key driver of CRC development is colon inflammatory responses especially in patients with inflammatory bowl disease (IBD). It has been proved that Panax notoginseng saponins (PNS) have anti-inflammatory, anti-oxidant and anti-tumor effects. The chemopreventive and immunomodulatory functions of PNS on colitis-associated colorectal cancer (CAC) have not been evaluated.This present study was designed to study the potential protective effects of PNS on AOM/DSS-induced CAC mice to explore the possible mechanism of PNS against CAC. Our study showed that PNS significantly alleviated colitis severity and prevented the occurrence of CAC. Functional assays revealed that PNS relieved immunosuppression of Treg cells in the CAC microenvironment by inhibiting the expression of IDO1 mediated directly by signal transducer and activator of transcription 1 (STAT1) rather than phosphorylated STAT1. Ultimately, Rh1, one of the PNS metabolites, exhibited the best inhibitory effect on IDO1 enzyme activity. Our study showed that PNS exerted significant chemopreventive function and immunomodulatory properties on CAC. It could reduce macrophages accumulation and Treg cells differentiation to reshape the immune microenvironment of CAC. These findings provided a promising approach for CAC intervention.
Subject(s)
Animals , Humans , Mice , Colitis/drug therapy , Colitis-Associated Neoplasms/drug therapy , Macrophages , Panax notoginseng , Saponins/therapeutic use , Tumor MicroenvironmentABSTRACT
As an essential amino acid, tryptophan (Trp) has various physiological functions and is of great significance in the metabolic process of tumors. In the human body, tryptophan is mainly transformed through kynurenine metabolic pathway, which not only promotes the inherent malignant properties of tumor cells, but also leads to immune-suppressive tumor microenvironment. Changes in tryptophan metabolism often occur in tumors, accompanied by abnormal gene expression of tryptophan-related enzymes, among which indoleamine 2,3-bioxygenase (IDO)-related gene expression and tryptophan 2,3-dioxygenase (TDO)-related gene changes are the most significant. A large number of clinical trials on IDO inhibitors, TDO inhibitors and combination therapy have been carried out. This paper reviewed the tryptophan metabolic pathway, regulation of IDO (TDO), kynurenine (KYN) and other related genes in tumor cells, and outlined the development of therapeutic schedule targeting tryptophan-related genes. The new progress provides new ideas for the further exploration of tumor treatment options.
ABSTRACT
Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the degradation of tryptophan to kynurenine. IDO1 is highly expressed in some tumor tissues. IDO1 can deplete tryptophan in tumor microenvironment, inhibit T cell function, and mediate the immune escape of tumor cells. Thus, IDO1 is considered a potential target of tumor immunotherapy. Currently, there are several IDO1 inhibitors in clinical research studies. The mechanism of IDO1-mediated tumor immune escape and the structure of IDO1 inhibitors are summarized in this review.
ABSTRACT
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme in the human tryptophan metabolism pathway, which can mediate tumor immune response. An IDO1 inhibitor would be a potential cancer immunotherapy drug. Based on the recently reported crystal of an IDO1 protein-inhibitor complex (PDBID: 6AZV), the structure of reported inhibitor, and by analyzing the interaction mode between the inhibitor and IDO1, new inhibitor molecules were designed and synthesized. All structures were confirmed by spectral data. Preliminary activity studies showed that compounds containing an azabiphenyl tetrazole structure (B1 and B2) and biphenyl compounds containing a sulfonamide structure (D1, D2 and D3) had excellent inhibitory activity of IDO1 at the enzyme and cell level, and were comparable or even better than the control drug INCB24360.
ABSTRACT
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of L-tryptophan metabolic oxidation pathway, in which the L-tryptophan is transformed into N-formyl kynurenine by oxidative cleavage. IDO1 is considered as a potential target for the development of cancer immunotherapeutic molecules. Up to now, at least 10 drug candidates have been advanced into clinical research. In this review, the binding mode and structure-activity relationships of the representative IDO1 small molecule inhibitors were summarized according the characteristics of chemical structures. Hopefully, this review could provide some insights for further development of novel IDO1 inhibitors.
ABSTRACT
Based on the reported IDO1 inhibitor U-3i,11 phenylsulfonamide derivatives were designed and syn-thesized by adopting bioisosterism and molecular docking technology.The inhibitory activities of the target compounds against IDO1 were determined by the HeLa cell-based kynurenine assay.The results demonstrated that most compounds showed different degrees of inhibitory effects on IDO1.Among them,compounds 3b and 3e displayed the most potent activity and could reverse IDO1-mediated immune suppression,which might be worth of further investigation.