Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1

Vladimir L. Kolossov, Nagendraprabhu Ponnuraj, Jessica N. Beaudoin, Matthew T. Leslie, Paul J. Kenis, H. Rex Gaskins

Research output: Contribution to journalArticle

Abstract

Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of EGSH in both the cytosol and mitochondrial matrix was observed in response to DNQ and β-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while β-lap elicits off-target responses at its effective doses.

Original languageEnglish (US)
Pages (from-to)680-686
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume483
Issue number1
DOIs
StatePublished - Jan 29 2017

Keywords

  • DNQ and β-lapachone
  • Lung and pancreatic cancer
  • NQO1
  • Redox homeostasis
  • roGFP2 redox probe

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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