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 A 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

Fingerprint

Quinones
Oxidation-Reduction
Glutathione
Oxidation
Dicumarol
Oxidative stress
Corrosion inhibitors
Substrates
Substrate Specificity
Sulfhydryl Compounds
Antineoplastic Agents
NAD
Cytosol
Oxidoreductases
Adenocarcinoma
Oxidative Stress
Lung
deoxynyboquinone
benzoquinone
Neoplasms

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

Cite this

Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1. / Kolossov, Vladimir L.; Ponnuraj, Nagendraprabhu; Beaudoin, Jessica N.; Leslie, Matthew T.; Kenis, Paul J A; Gaskins, H Rex.

In: Biochemical and Biophysical Research Communications, Vol. 483, No. 1, 29.01.2017, p. 680-686.

Research output: Contribution to journalArticle

Kolossov, Vladimir L. ; Ponnuraj, Nagendraprabhu ; Beaudoin, Jessica N. ; Leslie, Matthew T. ; Kenis, Paul J A ; Gaskins, H Rex. / Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1. In: Biochemical and Biophysical Research Communications. 2017 ; Vol. 483, No. 1. pp. 680-686.
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