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

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.

The diverse mechanisms and anticancer potential of naphthoquinones

“…might vary a lot compared to aqueous solutions [53]. Nevertheless, there are some groups of scientists which have been able to prove correlations between reduction/oxidation (redox) potentials of some naphthoquinones and the biological effect observed [76, 77], but in our experience this is not always the case.…”

“…Finally, deoxynyboquinone ( 33 ) was originally synthesized while studying the antibiotic nybomycin [116] and it has been reported to have a tenfold superior efficacy compared to that of β-lapachone ( 12 ) in killing different cancer cell lines in a NQO1-dependent manner [117]. Kolossov and collaborators further studied this compound to conclude that it is a more specific substrate of NQO1 and offered proof that it does not elicit off-target responses at effective concentrations, unlike β-lapachone ( 12 ) [77].…”