The NQO1 bioactivatable drug, ß-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism.
J Biol Chem
; 292(44): 18203-18216, 2017 11 03.
Article
em En
| MEDLINE
| ID: mdl-28916726
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. ß-Lapachone is bioactivated by NAD(P)Hquinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. ß-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 ß-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 ß-lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose responses of ß-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may have the potential to synergize with ß-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with ß-lapachone.
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MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Pró-Fármacos
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Naftoquinonas
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NAD(P)H Desidrogenase (Quinona)
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Metabolismo Energético
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Inibidores Enzimáticos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article