Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

Sci Rep. 2015 Nov 25:5:17066. doi: 10.1038/srep17066.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Catalase / genetics
  • Catalase / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Glycosylases / antagonists & inhibitors
  • DNA Glycosylases / metabolism
  • DNA Repair / drug effects*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Dicumarol / pharmacology
  • Female
  • Humans
  • Hydroxylamines / pharmacology
  • Hydroxylamines / therapeutic use
  • Mice
  • Mice, Nude
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Naphthoquinones / pharmacology
  • Naphthoquinones / therapeutic use
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism
  • Transplantation, Heterologous
  • X-ray Repair Cross Complementing Protein 1

Substances

  • DNA-Binding Proteins
  • Hydroxylamines
  • Naphthoquinones
  • Reactive Oxygen Species
  • X-ray Repair Cross Complementing Protein 1
  • XRCC1 protein, human
  • Xrcc1 protein, mouse
  • beta-lapachone
  • Dicumarol
  • methoxyamine
  • Catalase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Poly(ADP-ribose) Polymerases
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human