PCNA Inhibition Enhances the Cytotoxicity of β-Lapachone in NQO1-Positive Cancer Cells by Augmentation of Oxidative Stress-induced DNA Damage
dc.contributor.author | Su, Xiaolin | |
dc.contributor.author | Wang, Jiangwei | |
dc.contributor.author | Jiang, Lingxiang | |
dc.contributor.author | Chen, Yaomin | |
dc.contributor.author | Lu, Tao | |
dc.contributor.author | Mendonca, Marc S. | |
dc.contributor.author | Huang, Xiumei | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | |
dc.date.accessioned | 2023-09-07T17:56:57Z | |
dc.date.available | 2023-09-07T17:56:57Z | |
dc.date.issued | 2021 | |
dc.description.abstract | β-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. | |
dc.eprint.version | Author's manuscript | |
dc.identifier.citation | Su 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.2021.07.040 | |
dc.identifier.uri | https://hdl.handle.net/1805/35461 | |
dc.language.iso | en_US | |
dc.publisher | Elsevier | |
dc.relation.isversionof | 10.1016/j.canlet.2021.07.040 | |
dc.relation.journal | Cancer Letters | |
dc.rights | Publisher Policy | |
dc.source | PMC | |
dc.subject | NQO1 | |
dc.subject | β-Lapachone | |
dc.subject | PCNA | |
dc.subject | T2AA | |
dc.subject | Combination chemotherapy | |
dc.title | PCNA Inhibition Enhances the Cytotoxicity of β-Lapachone in NQO1-Positive Cancer Cells by Augmentation of Oxidative Stress-induced DNA Damage | |
dc.type | Article |