Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells

Abstract

Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

“…Numerous antitumor agents have been reported to increase ROS production in cancer cells . Different mechanisms have been studied, such as redox cycling and mitochondrial oxidase activation . Our results indicated that the most active gold(I) complex 4 b containing an OA derivative targets TrxR to induce ROS in A2780 cells and activate ROS‐dependent ERS activation.…”

“…Cancer cells generally have higher metabolic demands due to their highly proliferative nature. The thioredoxin system, including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, regulates cellular signal pathways and proliferation . TrxR is the only known physiological enzyme that can catalyze the reduction of oxidized Trx .…”

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

“…By employing characteristic intracellular and surrounding environments of cancer cells, prodrugs that could be selectively activated by cancer cells have attracted increasing interests in the past few years. 14,15 Based on the unique microenvironment of cancer cells, a large number of prodrugs that respond to different stimuli, such as thiols, [16][17][18][19] acidic pH, 20,21 ROS, 13,22,23 enzymes, 24,25 hypoxia 26,27 and light, [28][29][30] have been disclosed with great success in the experimental treatment of various cancer cells. Among different types of prodrugs, exploiting the disul-de scaffold as a trigger unit has been widely adopted, [16][17][18][19]31,32 as cancer cells usually have a higher ability than normal cells to reduce the disulde bond due to the elevated level of antioxidant molecules, such as thioredoxin (Trx), thioredoxin reductase (TrxR) and reduced glutathione (GSH).…”

“…31,[39][40][41][42][43] Depending on the ring size, cyclic disuldes/diselenides suffer from signicant ring tension and display different reactivity from acyclic disuldes/diselenides. [44][45][46][47] Encouraged by the recent work on employing a cyclic disulde moiety to construct uorescent probes and prodrugs, 24,44,[48][49][50] we report herein the construction of a seleno-prodrug Se-Gem ( Fig. 1) by introducing a 1,2-diselenolane (ve-membered cyclic diselenide) moiety into the anticancer drug gemcitabine (Gem; Fig.…”

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

“…Enzyme–substrate recognition between deoxycytidine kinase and GEM relies on hydrogen bonding between the 4‐NH 2 group of the nucleobase cytosine and Asp133, located in the active site of the enzyme . Chemically and enzymatically activatable GEM prodrugs have been developed by installing a protecting group onto the 4‐NH 2 group . Thus, A‐GEM was also designed by masking the same position in GEM with a boronate‐ester‐based carbamate protecting group (Figure ).…”