Metabolism as a key to histone deacetylase inhibition
Year: 2011
Type: review
Abstract: There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a "direct acting" compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-α-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin-yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future.
Authors: Praveen Rajendran, David E. Williams, Emily Ho, Roderick H. Dashwood
Institution: Oregon State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1080112686, BETA CATENIN MUTATION IN PHIP AND IQ INDUCED COLON CA, G132102914, Modulation of Colon Carcinogenesis by Chlorophyllin, Reducing Susceptibility to Environmental Stress Throughout the Life Span, G49960215, G546173785, Dietary histone deactylase inhibitors in prostate cancer prevention, CCAR2 as a Target for Prevention of Colorectal Cancer., Comparative Mechanisms of Cancer Chemoprevention, G8369413267, MODULATION OF COLON CARCINOGENESIS BY CHLOROPHYLLIN, G8970073277
OpenAlex ID: W2024473923