Discovery of gliotoxin as a new small molecule targeting thioredoxin redox system.

Thioredoxin redox system has been implicated as an intracellular anti-oxidant defense system leading to reduction of cellular oxidative stresses utilizing electrons from NADPH. From high content screening of small molecules targeting the system, gliotoxin, a fungal metabolite, was identified as an active compound. Gliotoxin potently accelerates NADPH oxidation and reduces H(2)O(2). The compound reduces H(2)O(2) to H(2)O by replacing the function of peroxiredoxin in vitro and decreases intracellular level of H(2)O(2) in HeLa cells. The anti-oxidant activity of gliotoxin was further validated H(2)O(2)-mediated cellular phenotype of angiogenesis. The proliferation of endothelial cells was inhibited by the compound at nanomolar range. In addition, H(2)O(2)-induced tube formation and invasion of the cells were blocked by gliotoxin. Together, these results demonstrate that gliotoxin is a new small molecule targeting thioredoxin redox system.