Design and discovery of novel small molecule modulators of reactive oxygen species-mediated cell signaling

Oxidative stress is an important hallmark of cancer. Elevated levels of intrinsic reactive oxygen species (ROS) make tumor cells more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death. Increasing ROS production or decreasing ROS scavengers shows potential for selectively targeting tumor cells that are under persistent oxidative stress. Recently, we have discovered novel class of quinazolinediones that exert their anticancer effects by modulating ROS-mediated cell signaling.The sub-micromolar anti-proliferative properties of these compounds were demonstrated by MTT and colony formation assays in a panel of cancer cell lines of different origins. Treatment with these agents induced cell cycle arrest, and increased superoxide production in cancer cells. Furthermore, proteomics analysis of 600 target antibody array revealed that these molecules significantly affected several cell signaling pathways implicated in carcinogenesis, cancer progression, redox signaling, and cell death.In conclusion, quinazolinediones are promising lead compounds that selectively enhance ROS production and induce ROS-mediated cell death in cancer cells, and warrant further preclinical studies.