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.

Recent Development of Prodrugs of Gemcitabine

“…Xinming Li et al designed a prodrug of GCB, termed S-Gem ( Figure 2 A), whose enzymatic activation can be triggered by thioredoxin reductase (TrxR) [ 7 ]. Malignant cancer cells have abnormally high levels of TrxR for maintaining their tumor phenotypes [ 8 ]; thus, it was hypothesized that prodrug activation would be selectively achieved inside the cancer cells.…”

How can we improve the design of small molecules to target thioredoxin reductase for treating cancer?

“…In our efforts to develop the TRFS series fluorescent probes of TrxR, we disclosed that the 1,2-dithiolane (five-membered cyclic disulfide) scaffold could be reduced by TrxR exclusively [15,16]. Based on this discovery, we prepared a first TrxR-dependent prodrug S-Gem and demonstrated that S-Gem shows TrxR-dependent cytotoxicity [17]. Compared to the inhibition of TrxR for cancer treatment, the success of S-Gem provides a completely new strategy to develop therapeutic molecules that target TrxR.…”

Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically

“…In contrast however, 1,2-dithiolanes have also been reported as reduction-sensing units with a remarkable selectivity for TrxR. The fluorogenic TRFS-probes 16 , 18 , 45 , 46 and prodrugs 17 have been widely used for cellular studies, commercialised, and reviewed 47 – 51 (Fig. 1e ; overview in Supplementary Fig.…”