Natural Molecules Targeting Thioredoxin System and Their Therapeutic Potential

Discovery of hydroxytyrosol as thioredoxin reductase 1 inhibitor to induce apoptosis and G1/S cell cycle arrest in human colorectal cancer cells via ROS generation

“…As presented in Fig. 5A , HT was indicated to form hydrogen bonds with Sec498, Cys497, Gln494 and Trp407 residues of the C-terminal active site of the redox center of TrxR1 ( 34 , 36-39 ). Thus, the proposed reaction mechanism for HT is the simultaneous inhibition of the adjacent C-terminal active site residues of TrxR1, which is expected to effectively suppress TrxR1 activity.…”

“…The major function of TrxR1 is to maintain Trx in a reduced state and prevent oxidative stress ( 34 ). Having confirmed that HT was a potent TrxR1 inhibitor, the levels of ROS were then determined in HCT-116 and SW620 cells.…”

Onopordopicrin from the new genus Shangwua as a novel thioredoxin reductase inhibitor to induce oxidative stress-mediated tumor cell apoptosis

“…As one of the essential antioxidant enzymes in cells is TrxR. If the TrxR activity is inhibited, the intracellular antioxidant capacity for tumor cells is partially lessened, thereby causing the above-mentioned substantial accumulation of ROS 39 , 50 . We thus examined the effect of ONP on cellular TrxR activity.…”

“…Functionally, in addition to the key role of TrxR in redox regulation 20,21 , an ever-widening range of evidence has supported that TrxR highly enriched in many tumor types is essentially implicated with multiple steps of tumorigenesis and development [20][21][22][23] , and is a potential and promising target for the current anticancer drugs discovery [24][25][26][27] . As our continuing efforts in discovering therapeutic molecules derived from natural products that effectively interfere with cellular redox signaling [28][29][30][31][32][33][34][35][36][37][38][39] , we assessed herein the antitumor activity of ONP, C2 and C3, and systematically reported a new mechanism by which ONP targets intracellular TrxR inhibition to cause oxidative stress-mediated tumor cell apoptosis. Mechanistically, the b-carbocation of the lactone ring in ONP covalently bound to the redox-active Sec residue at the C-terminus of TrxR, thereby leading to a decrease in TrxR activity.…”

Cyclic 5-Membered Disulfides Are Not Selective Substrates of Thioredoxin Reductase, but Are Opened Nonspecifically by Thiols

“…30,31 In contrast however, 1,2-dithiolanes have also been reported as reduction-sensing units with a remarkable selectivity for TrxR. The fluorogenic TRFS probes 14,16,32,33 and prodrugs 15 have been commercialised and extensively reviewed [34][35][36][37][38] (Fig 1e; overview in Fig S1b). These probes have since been used to study the role of TrxR in Parkinson's disease 39 and stroke 33 , and have been employed for mechanistic validation of putative TrxR inhibitors during screening approaches.…”