# PubMed- NOX NADPH oxidase isoforms are inhibited by celastrol with a dual mode of action.



## VSsupport (Feb 12, 2008)

[TD]
*NOX NADPH oxidase isoforms are inhibited by celastrol with a dual mode of action.*

Br J Pharmacol. 2011 Apr 18;

Authors: Jaquet V, Marcoux J, Forest E, Leidal KG, McCormick S, Westermaier Y, Perozzo R, Plastre O, Fioraso-Cartier L, Diebold B, Scapozza L, Nauseef WM, Fieschi F, Krause KH, Bedard K

Background: Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions, and shows benefits in models of neurodegenerative disease, cancer and arthritis, although its mechanism of action is incompletely understood. Experimental Approach: Celastrol was tested on human NOX NADPH oxidases using a panel of experiments: production of reactive oxygen species and oxygen consumption by NOX enzymes, xanthine oxidase activity, cell toxicity, phagocyte oxidase subunit translocation, and binding to cytosolic subunits of NOX enzymes. The effect of celastrol was compared to diphenyleneiodonium, an established inhibitor of flavoproteins. Key Results: Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with dose response curves exhibiting higher Hill coefficients and lower IC(50) values for NOX1 and NOX2 compared to NOX4 and NOX5, suggesting differences in their mode of action. In a cell-free system, celastrol had an IC(50) of 1.24 and 8.4 µM for NOX2 and NOX5, respectively. Cytotoxicity, oxidant scavenging, and inhibition of p47(phox) translocation could not account for NOX inhibition. Celastrol bound to a recombinant p47(phox) and disrupted the binding of the proline rich region of p22(phox) to the tandem SH3 domain of p47(phox) and NOXO1, the cytosolic subunits of NOX2 and NOX1 respectively. Conclusions and Implications: These results demonstrate that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome.

PMID: 21501142 [PubMed - as supplied by publisher]

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