RESUMO
BACKGROUND: ß-lapachone (ß-lap), the NQO1 bioactivatable drug, is thought to be a promising anticancer agent. However, the toxic side effects of ß-lap limit the drug use, highlighting the need for a thorough understanding of ß-lap's mechanism of action. ß-lap undergoes NQO1-dependent futile redox cycling, generating massive ROS and oxidative DNA lesions, leading to cell death. Thus, base excision repair (BER) pathway is an important resistance factor. XRCC1, a scaffolding component, plays a critical role in BER. METHODS: We knocked down XRCC1 expression by using pLVX-shXRCC1 in the MiaPaCa2 cells and BxPC3 cells and evaluated ß-lap-induced DNA lesions by γH2AX foci formation and alkaline comet assay. The cell death induced by XRCC1 knockdown + ß-lap treatment was analysed by relative survival, flow cytometry and Western blotting analysis. RESULTS: We found that knockdown of XRCC1 significantly increased ß-lap-induced DNA double-strand breaks, comet tail lengths and cell death in PDA cells. Furthermore, we observed combining XRCC1 knockdown with ß-lap treatment switched programmed necrosis with ß-lap monotherapy to caspase-dependent apoptosis. CONCLUSIONS: These results indicate that XRCC1 is involved in the repair of ß-lap-induced DNA damage, and XRCC1 loss amplifies sensitivity to ß-lap, suggesting targeting key components in BER pathways may have the potential to expand use and efficacy of ß-lap for gene-based therapy.