Journal
CHEMISTRY & BIOLOGY
Volume 22, Issue 4, Pages 439-445Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2015.03.014
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Funding
- Stanley Medical Research Institute
- Burke Foundation
- NIH [P01 NIA AG014930]
- Miriam and Sheldon Adelson Medical Research Foundation Grant
- Goldsmith Foundation post-doctoral fellowship
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Histone deacetylase (HDAC) inhibitors have shown enormous promise for treating various disease states, presumably due to their ability to modulate acetylation of histone and non-histone proteins. Many of these inhibitors contain functional groups capable of strongly chelating metal ions. We demonstrate that several members of one such class of compounds, the hydroxamate-based HDAC inhibitors, can protect neurons from oxidative stress via an HDAC-independent mechanism. This previously unappreciated antioxidant mechanism involves the in situ formation of hydroxamate-iron complexes that catalyze the decomposition of hydrogen peroxide in a manner reminiscent of catalase. We demonstrate that while many hydroxamate-containing HDAC inhibitors display a propensity for binding iron, only a subset form active catalase mimetics capable of protecting neurons from exogenous H2O2. In addition to their impact on stroke and neurodegenerative disease research, these results highlight the possibility that HDAC-independent factors might play a role in the therapeutic effects of hydroxamate-based HDAC inhibitors.
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