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

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.
AuthorsGaurab Chakrabarti, Molly A Silvers, Mariya Ilcheva, Yuliang Liu, Zachary R Moore, Xiuquan Luo, Jinming Gao, Glenda Anderson, Lili Liu, Venetia Sarode, David E Gerber, Sandeep Burma, Ralph J DeBerardinis, Stanton L Gerson, David A Boothman
JournalScientific reports (Sci Rep) Vol. 5 Pg. 17066 (Nov 25 2015) ISSN: 2045-2322 [Electronic] England
PMID26602448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • Animals
  • Autophagy (drug effects)
  • Catalase (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • DNA Breaks, Double-Stranded (drug effects)
  • DNA Glycosylases (antagonists & inhibitors, metabolism)
  • DNA Repair (drug effects)
  • DNA-Binding Proteins (antagonists & inhibitors, metabolism)
  • Dicumarol (pharmacology)
  • Female
  • Humans
  • Hydroxylamines (pharmacology, therapeutic use)
  • Mice
  • Mice, Nude
  • NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors, metabolism)
  • Naphthoquinones (pharmacology, therapeutic use)
  • Pancreatic Neoplasms (drug therapy, metabolism, pathology)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Transplantation, Heterologous
  • X-ray Repair Cross Complementing Protein 1

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