The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation.
Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) is the lead compound of a new class of histone deacetylase (HDAC) inhibitors used as anticancer drugs that have been shown to affect multiple proteins associated with gene expression, cell proliferation, and migration. Studies have also demonstrated the essential role of the hydroxamate moiety of SAHA in HDAC inhibition. The ability of SAHA and its structural analog trichostatin A (TSA) to generate NO upon oxidation was tested directly, by spin trapping of NO using electron paramagnetic resonance spectroscopy, and also indirectly, via the determination of nitrite using the Griess assay. H2O2/metmyoglobin was used to oxidize SAHA and TSA. These studies demonstrate, for the first time, the release of NO from SAHA and its structural analog TSA. We tested the protective effects of SAHA, TSA, and valproic acid (VPA) in mammalian Chinese hamster V79 cells exposed to a bolus of H2O2 for 1 h and monitored the clonogenic cell survival. Both SAHA and TSA afforded significant cytoprotection when co-incubated with H2O2, whereas VPA was ineffective. These studies provide evidence for the release of NO by hydroxamate-containing HDAC inhibitors and their antioxidant effects. Such roles may be an added advantage of this class of HDAC agents used for epigenetic therapies in cancer.
Samuni
Yuval
Y
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Flores-Santana
Wilmarie
W
Krishna
Murali C
MC
Mitchell
James B
JB
Wink
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004578:Electron Spin Resonance Spectroscopy; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008786:Metmyoglobin / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D000077337:Vorinostat
D000970:Antineoplastic Agents; D000975:Antioxidants; D006877:Hydroxamic Acids; D008786:Metmyoglobin; D009569:Nitric Oxide; C012589:trichostatin A; D000077337:Vorinostat; D006861:Hydrogen Peroxide; D006655:Histone Deacetylases