The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1 pancreatic cancer cells, causing perturbation in central carbon metabolism

Molly A. Silvers, Stanislaw Deja, Naveen Singh, Robert A. Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S. Beg, Shawn C. Burgess, Ralph J. DeBerardinis, David A. Boothman, Matthew E. Merritt

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause offtarget toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD+/ATP depletion. However, the effects of this drug on energy metabolism due to NAD+ depletion were never described. The futile redox cycle rapidly consumes O2, rendering standard assays of Krebs cycle turnover unusable. In this study, a multimodal analysis, including metabolic imaging using hyperpolarized pyruvate, points to reduced oxidative flux due to NAD+ depletion after β-lapachone treatment of NQO1+ human pancreatic cancer cells. NAD+-sensitive pathways, such as glycolysis, flux through lactate dehydrogenase, and the citric acid cycle (as inferred by flux through pyruvate dehydrogenase), were down-regulated byβ-lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose responses of β-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may have the potential to synergize with β-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with β-lapachone.

Original languageEnglish (US)
Pages (from-to)18203-18216
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number44
DOIs
StatePublished - Nov 3 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1 pancreatic cancer cells, causing perturbation in central carbon metabolism'. Together they form a unique fingerprint.

  • Cite this