Su, XiaolinWang, JiangweiJiang, LingxiangChen, YaominLu, TaoMendonca, Marc S.Huang, Xiumei2023-09-072023-09-072021Su X, Wang J, Jiang L, et al. PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage. Cancer Lett. 2021;519:304-314. doi:10.1016/j.canlet.2021.07.040https://hdl.handle.net/1805/35461β-Lapachone is a classic quinone-containing antitumor NQO1-bioactivatable drug that directly kills NQO1-overexpressing cancer cells. However, the clinical applications of β-lapachone are primarily limited by its high toxicity and modest lethality. To overcome this side effect and expand the therapeutic utility of β-lapachone, we demonstrate the effects of a novel combination therapy including β-lapachone and the proliferating cell nuclear antigen (PCNA) inhibitor T2 amino alcohol (T2AA) on various NQO1+ cancer cells. PCNA has DNA clamp processivity activity mediated by encircling double-stranded DNA to recruit proteins involved in DNA replication and DNA repair. In this study, we found that compared to monotherapy, a nontoxic dose of the T2AA synergized with a sublethal dose of β-lapachone in an NQO1-dependent manner and that combination therapy prevented DNA repair, increased double-strand break (DSB) formation and PARP1 hyperactivation and induced catastrophic energy loss. We further determined that T2AA promoted programmed necrosis and G1/S phase cell cycle arrest in β-lapachone-treated NQO1+ cancer cells. Our findings show novel evidence for a new therapeutic approach that combines of β-lapachone treatment with PCNA inhibition that is highly effective in treating NQO1+ solid tumor cells.en-USPublisher PolicyNQO1β-LapachonePCNAT2AACombination chemotherapyArticle