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Pharmacological Characterization of the Seven Human NOX Isoforms and Their Inhibitors

Pharmacological Characterization of the Seven Human NOX Isoforms and Their Inhibitors

Fiona Augsburger, Aleksandra Filippova, Delphine Rasti, Tamara Seredenina, Magdalena Lam, Ghassan Maghzal, Zahia Mahiout, Pidder Jansen-Dürr, Ulla G Knaus, James Doroshow, Roland Stocker, Karl-Heinz Krause, etc.

Redox Biol. 2019 Sep;26:101272.

PMID: 31330481

Abstract:

Background:
NADPH oxidases (NOX) are a family of flavoenzymes that catalyze the formation of superoxide anion radical (O2•-) and/or hydrogen peroxide (H2O2). As major oxidant generators, NOX are associated with oxidative damage in numerous diseases and represent promising drug targets for several pathologies. Various small molecule NOX inhibitors are used in the literature, but their pharmacological characterization is often incomplete in terms of potency, specificity and mode of action.
Experimental approach:
We used cell lines expressing high levels of human NOX isoforms (NOX1-5, DUOX1 and 2) to detect NOX-derived O2•- or H2O2 using a variety of specific probes. NOX inhibitory activity of diphenylene iodonium (DPI), apocynin, diapocynin, ebselen, GKT136901 and VAS2870 was tested on NOX isoforms in cellular and membrane assays. Additional assays were used to identify potential off target effects, such as antioxidant activity, interference with assays or acute cytotoxicity.
Key results:
Cells expressing active NOX isoforms formed O2•-, except for DUOX1 and 2, and in all cases activation of NOX isoforms was associated with the detection of extracellular H2O2. Among all molecules tested, DPI elicited dose-dependent inhibition of all isoforms in all assays, however all other molecules tested displayed interesting pharmacological characteristics, but did not meet criteria for bona fide NOX inhibitors.
Conclusion:
Our findings indicate that experimental results obtained with widely used NOX inhibitors must be carefully interpreted and highlight the challenge of developing reliable pharmacological inhibitors of these key molecular targets.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP29799222	Diapocynin		29799-22-2	Price
AP722456317	VAS2870		722456-31-7	Price

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