Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy
Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude identifie des molécules capables d'inhiber de façon spécifique et irréversible la thiorédoxine réductase de type 1 du cytosol, puis analyse leur efficacité thérapeutique et leur toxicité
Oxidative stress is a common feature of the tumor microenvironment, and the tumor cells adapt to it by activating the glutathione and thioredoxin antioxidant pathways. However, noncancer cells also require these pathways for survival, and inhibiting both pathways simultaneously can cause unacceptable toxicity. Instead, Stafford et al. decided to target the thioredoxin pathway alone in an effort to kill cancer cells with less collateral damage. Through a large-scale screening effort, the authors identified candidate inhibitors of the enzyme thioredoxin reductase 1 and then demonstrated their biological effects and anticancer efficacy in vitro and in multiple mouse models.Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets. For our lead compounds, TXNRD1 inhibition correlated with cancer cell cytotoxicity, and inhibitor-triggered conversion of TXNRD1 from an antioxidant to a pro-oxidant enzyme correlated with corresponding increases in cellular production of H2O2. In mice, the most specific TXNRD1 inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1), impaired growth and viability of human tumor xenografts and syngeneic mouse tumors while having little mitochondrial toxicity and being better tolerated than auranofin. These results display the therapeutic anticancer potential of irreversibly targeting cytosolic TXNRD1 using small molecules and present potent and selective TXNRD1 inhibitors. Given the pronounced up-regulation of TXNRD1 in several metastatic malignancies, it seems worthwhile to further explore the potential benefit of specific irreversible TXNRD1 inhibitors for anticancer therapy.