Novel NQO1 specific anti-tumor agent, S3001-SD, induces selective cancer cell cytotoxicity

We characterized the effect of a novel synthetic NQO1 substrate S3001-SD, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1. S3001-SD increases O2 consumption and ROS production; induces depletion of NAD+ and NADH; causes PARP hyperactivation; halts mRNA translation and protein synthesis, eventually leading to a unique form of caspase-independent cell death. S3001-SD and beta-lapachone share substantial similarities in vitro and both drugs elicit their response through NQO1. Transcriptional profiling and gene set enrichment analysis revealed that S3001-SD and beta-lapachone regulates almost identical pathways, including mTOR1 signaling, oxidative phosphorylation, and p53 pathway.