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

J Biol Chem. 2017 Nov 3;292(44):18203-18216. doi: 10.1074/jbc.M117.813923. Epub 2017 Sep 15.

Abstract

Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target 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 by β-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.

Keywords: anaerobic glycolysis; drug metabolism; energy metabolism; isotopic tracer; nicotinamide adenine dinucleotide (NAD); nuclear magnetic resonance (NMR); oxidation-reduction (redox); oxidative stress; pyruvate; pyruvate dehydrogenase complex (PDC).

Publication types

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

MeSH terms

  • Activation, Metabolic
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Biomarkers / metabolism
  • Carbon Isotopes
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Citric Acid Cycle / drug effects
  • DNA Damage
  • Energy Metabolism / drug effects*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glycolysis / drug effects
  • Humans
  • Metabolomics / methods
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Naphthoquinones / metabolism
  • Naphthoquinones / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / metabolism
  • Principal Component Analysis
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Carbon Isotopes
  • Enzyme Inhibitors
  • Naphthoquinones
  • Neoplasm Proteins
  • Prodrugs
  • Recombinant Proteins
  • beta-lapachone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human