Cytotoxic and Radiosensitising Effects of a Novel Thioredoxin Reductase Inhibitor in Brain Cancers

Abstract

The thioredoxin (Trx) system, a key antioxidant pathway, represents an attractive target for cancer therapy. This study investigated the chemotherapeutic and radiosensitising effects of a novel Trx reductase (TrxR) inhibitor, IQ10, on brain cancer cells and the underlying mechanisms of action. Five brain cancer cell lines and a normal cell type were used. TrxR activity and expression were assessed by insulin reduction assay and Western blotting, respectively. IQ10 cytotoxicity was evaluated using growth curve, resazurin reduction and clonogenic assays. Radiosensitivity was examined using clonogenic assay. Reactive oxygen species levels were examined by flow cytometry and DNA damage assessed by immunofluorescence. Epithelial-mesenchymal transition (EMT)-related gene expression was examined by RT-PCR array. IQ10 significantly inhibited TrxR activity but did not affect Trx system protein expression in brain cancer cells. The drug exhibited potent anti-proliferative and cytotoxic effects against brain cancer cells under both normoxic and hypoxic conditions in both 2D and 3D systems, with IC50s in the low micromolar range. It was up to ~ 1000-fold more potent than temozolomide. IQ10 substantially sensitised various brain cancer cells to radiation, with such effect being due, in part, to functional inhibition of TrxR, making cells less able to deal with oxidative stress and leading to increased oxidative DNA damage. IQ10 significantly downregulated EMT-associated gene expression suggesting potential anti-invasive and antimetastatic properties. This study suggests that IQ10 is a potent anticancer agent and could be used as either a single agent or combined with radiation, to treat brain cancers.