Abstract
Backgroundβ-lapachone (β-lap), the NQO1 bioactivatable drug, is thought to be a promising anticancer agent. However, the toxic side effects of β-lap limit the drug use, highlighting the need for a thorough understanding of β-lap’s mechanism of action. β-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.MethodsWe knocked down XRCC1 expression by using pLVX-shXRCC1 in the MiaPaCa2 cells and BxPC3 cells and evaluated β-lap-induced DNA lesions by γH2AX foci formation and alkaline comet assay. The cell death induced by XRCC1 knockdown + β-lap treatment was analysed by relative survival, flow cytometry and Western blotting analysis.ResultsWe found that knockdown of XRCC1 significantly increased β-lap-induced DNA double-strand breaks, comet tail lengths and cell death in PDA cells. Furthermore, we observed combining XRCC1 knockdown with β-lap treatment switched programmed necrosis with β-lap monotherapy to caspase-dependent apoptosis.ConclusionsThese results indicate that XRCC1 is involved in the repair of β-lap-induced DNA damage, and XRCC1 loss amplifies sensitivity to β-lap, suggesting targeting key components in BER pathways may have the potential to expand use and efficacy of β-lap for gene-based therapy.
Highlights
Pancreatic cancer is classified as pancreatic ductal adenocarcinoma (PDA) due to more than 90% of pancreatic cancer having ductal morphology [1]
For all four tested pancreatic cancer cell lines, cell death happened in an NAD(P)H: quinone oxidoreductase 1 (NQO1)-dependent manner, as dicoumarol (DIC, an NQO1 inhibitor) treatment (Figs. 1B~ D) or S2–013 cells (NQO1-deficient cells, Fig. 1E) remained nonresponsive to β-lap, suggesting low NQO1 expression spared cells from lethality induced by β-lap
These results demonstrated that the sensitivity to β-lap was associated with the expression of NQO1
Summary
Pancreatic cancer is classified as pancreatic ductal adenocarcinoma (PDA) due to more than 90% of pancreatic cancer having ductal morphology [1]. PDA is currently ranked as the fourth leading cause of cancer mortality in the United States [2]. The main cure for PDA is surgical resection with low survival rates [3]. It is imperative to develop novel effective strategies to treat PDA. Current chemotherapy achieves significant clinical benefit, but lacking tumor-selectivity often results in undesirable off-target toxicities in normal, healthy tissue, highlighting the need for gene-based treatment [4]. Β-lapachone (β-lap, in clinical form, ARQ761), a tumor-selective drug, is a NAD(P)H: quinone oxidoreductase 1 (NQO1) bioactivatable drug. NQO1 is highly expressed in many cancers. NQO1 is highly expressed in many cancers. 90% of pancreatic and NSCL
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