1. The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism.
- Author
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Silvers MA, Deja S, Singh N, Egnatchik RA, Sudderth J, Luo X, Beg MS, Burgess SC, DeBerardinis RJ, Boothman DA, and Merritt ME
- Subjects
- Activation, Metabolic, Antineoplastic Agents metabolism, Biomarkers metabolism, Carbon Isotopes, Cell Line, Tumor, Cell Survival drug effects, Citric Acid Cycle drug effects, DNA Damage, Enzyme Inhibitors metabolism, Glycolysis drug effects, Humans, Metabolomics methods, NAD(P)H Dehydrogenase (Quinone) genetics, NAD(P)H Dehydrogenase (Quinone) metabolism, Naphthoquinones metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Oxidation-Reduction, Oxidative Stress drug effects, Pancreatic Neoplasms enzymology, Pancreatic Neoplasms metabolism, Principal Component Analysis, Prodrugs metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Antineoplastic Agents pharmacology, Energy Metabolism drug effects, Enzyme Inhibitors pharmacology, NAD(P)H Dehydrogenase (Quinone) antagonists & inhibitors, Naphthoquinones pharmacology, Pancreatic Neoplasms drug therapy, Prodrugs pharmacology
- 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., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.) more...- Published
- 2017
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