Hydroxamate-based histone deacetylase inhibitors can protect neurons from oxidative stress via a histone deacetylase-independent catalase-like mechanism

David Olson, Sama F. Sleiman, Megan W. Bourassa, Florence F. Wagner, Jennifer P. Gale, Yan Ling Zhang, Rajiv R. Ratan, Edward B. Holson

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)439-445
Number of pages7
JournalChemistry and Biology
Volume22
Issue number4
DOIs
StatePublished - Apr 23 2015
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Histone Deacetylases
Oxidative stress
Catalase
Neurons
Oxidative Stress
Neurodegenerative diseases
Acetylation
Therapeutic Uses
Chelation
Neurodegenerative Diseases
Histones
Hydrogen Peroxide
Functional groups
Metal ions
Iron
Antioxidants
Metals
Stroke
Ions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Hydroxamate-based histone deacetylase inhibitors can protect neurons from oxidative stress via a histone deacetylase-independent catalase-like mechanism. / Olson, David; Sleiman, Sama F.; Bourassa, Megan W.; Wagner, Florence F.; Gale, Jennifer P.; Zhang, Yan Ling; Ratan, Rajiv R.; Holson, Edward B.

In: Chemistry and Biology, Vol. 22, No. 4, 23.04.2015, p. 439-445.

Research output: Contribution to journalArticle

Olson, David ; Sleiman, Sama F. ; Bourassa, Megan W. ; Wagner, Florence F. ; Gale, Jennifer P. ; Zhang, Yan Ling ; Ratan, Rajiv R. ; Holson, Edward B. / Hydroxamate-based histone deacetylase inhibitors can protect neurons from oxidative stress via a histone deacetylase-independent catalase-like mechanism. In: Chemistry and Biology. 2015 ; Vol. 22, No. 4. pp. 439-445.
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