ABSTRACT
In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 µM) and TrxR1 (IC50 = 3.00 ± 0.25 µM) were selected for further evaluation. Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced apoptosis and G1/S cell cycle arrest in cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.
Subject(s)
Colorectal Neoplasms , Enzyme Inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase , Reactive Oxygen Species , Thioredoxin Reductase 1 , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Thioredoxin Reductase 1/antagonists & inhibitors , Cell Line, Tumor , Humans , Apoptosis/drug effects , Colorectal Neoplasms/enzymologyABSTRACT
OBJECTIVE: To explore the efficacy and action mechanism of penetrating moxibustion at governor vessel for persistent allergic rhinitis of deficiency-cold syndrome. METHODS: Ninety patients with persistent allergic rhinitis of deficiency-cold syndrome were randomly divided into an observation group (n = 45) and a control group (n = 45). The patients in the control group were treated with momethasone furoate nasal spray, 2 sprays per side per time, once a day. On the basis of treatment in the control group, the patients in the observation group were additionally treated with penetrating moxibustion at governor vessel, 2 h per treatment, once a week. Both groups were treated for 4 weeks. The TCM symptom score, visual analogue scale (VAS) score and rhinoconjunctivitis quality of life questionnaire (RQLQ) score were observed in the two groups before and after treatment. The serum level of immunoglobulin E (IgE) and complete blood count of eosinophil (EOS) were measured before and after treatment, and the clinical effects were compared. RESULTS: Compared before treatment, the TCM symptom scores, VAS scores, RQLQ scores, serum levels of IgE and complete blood count of EOS in the two groups were all reduced after treatment (P<0.05), and those in the observation group were lower than those in the control group (P<0.05). The total effective rate in the observation group was 95.6% (43/45), which was higher than 82.2% (37/45) in the control group (P<0.05). CONCLUSION: Based on the momethasone furoate nasal spray, the adjuvant treatment of penetrating moxibustion at governor vessel could significantly improve the clinical symptoms in patients with persistent allergic rhinitis of deficiency-cold syndrome, and its mechanism may be related to the regulation of immune disorder.
