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
Pulmonary fibrosis is a progressive interstitial lung disease with poor prognosis. Anemarrhenae Rhizoma is a traditional Chinese herbal medicine and has been applied in clinical practice for a long history. Recently, components of Anemarrhenae Rhizoma were reported to possess anti-inflammatory and immunomodulatory features; however, the effect of them on pulmonary fibrosis remains unknown. In this study, we explored the therapeutic effect of total extract of Anemarrhenae Rhizoma (TEAR) on bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis rat model was established by a single intratracheal instillation of bleomycin, three doses of TEAR were intragastrically administered for consecutive 28 days. Subsequent to sacrificing of rats, pulmonary fibrosis was observed in rats treated with bleomycin, but administration of TEAR attenuated lung fibrosis, as evidenced by the improved lung histopathological damage and decreased weight loss and lung index. Moreover, TEAR treatment inhibited the inflammatory response in lung fibrosis, which was shown by the reduced nitrogen oxide level and myeloperoxidase activity. Furthermore, TEAR modulated the redox balance in lung tissue by alleviated lipid peroxidation and enhanced enzymatic antioxidants activity. Meanwhile, TEAR protected the rats from fibrosis in a dose-dependent manner, and the anti-fibrotic activity of TEAR may be related to the modulation of TGF-ß1/Smad signaling pathway. Collectively, TEAR alleviates bleomycin-induced pulmonary fibrosis, indicating perspectives for development of a potential agent for lung fibrosis therapy.
