TRAIL-Based High Throughput Screening Reveals a Link between TRAIL-Mediated Apoptosis and Glutathione Reductase, a Key Component of Oxidative Stress Response

摘要: A high throughput screen for compounds that induce TRAIL-mediated apoptosis identified ML100 as an active chemical probe, which potentiated TRAIL activity in prostate carcinoma PPC-1 and melanoma MDA-MB-435 cells. Follow-up silico modeling profiling cell-based assays allowed us to identify NSC130362, pharmacophore analog of induced 65-95% cytotoxicity cancer cells did not affect the viability human primary hepatocytes. In agreement with activation apoptotic pathway, both NSC130362 synergistically caspase-3/7 Subsequent affinity chromatography inhibition studies convincingly demonstrated glutathione reductase (GSR), a key component oxidative stress response, is target NSC130362. accordance role GSR gene silencing but Inhibition resulted induction stress, was evidenced by increase intracellular reactive oxygen species (ROS) peroxidation mitochondrial membrane after treatment The antioxidant reduced (GSH) fully protected from cell lysis TRAIL, thereby further confirming interplay between TRAIL. As consequence combined different inducers promoted death variety hepatocytes vivo, mouse tumor xenograft model.