ArticleScientific reports2015
Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 60 citations in OpenAlex.
- Article
- In Vitro Evaluation of Natural Sesquiterpene Lactones and Naphthoquinones Against Pancreatic Ductal Adenocarcinoma Cells.Molecules (Basel, Switzerland) · 2026Article
- New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Emerging pathways yielding opportunities for future treatments in pancreatic ductal adenocarcinoma.Expert opinion on therapeutic targets · 2025Review
- Unraveling systemic responses to NQO1-activated IB-DNQ and Rucaparib single and dual agent therapy in triple-negative breast cancers.bioRxiv : the preprint server for biology · 2025Article
- Repurposing Artemisinin-Based Drugs from Antimalarial to Pan-Therapeutic: Pharmacological Promise and Therapeutic Challenges.Drug design, development and therapy · 2025Review
- Article
- β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Review
- Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.Nutrients · 2022Article
- Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases.Life (Basel, Switzerland) · 2021Review
- X-ray repair cross-complementing protein 1 (XRCC1) loss promotes β-lapachone -induced apoptosis in pancreatic cancer cells.BMC cancer · 2021Article
- Measuring NQO1 Bioactivation Using [Cancers · 2021Article
- The diverse functionality of NQO1 and its roles in redox control.Redox biology · 2021Review
- β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation.Frontiers in oncology · 2021Article
- DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition.Scientific reports · 2020Article
- Inhibitors of DNA Glycosylases as Prospective Drugs.International journal of molecular sciences · 2020Review
- Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy.JCI insight · 2020Article
- Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone.Redox biology · 2020Article
- NQO1 is a determinant for cellular sensitivity to anti-tumor agent Napabucasin.American journal of cancer research · 2020Article
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H: Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD(+)/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. SIGNIFICANCE: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.
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