Harnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer

Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds