Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention?
There is growing interest in the various mechanisms that regulate chromatin remodeling, including modulation of histone deacetylase (HDAC) activities. Competitive HDAC inhibitors disrupt the cell cycle and/or induce apoptosis via de-repression of genes such as P21 and BAX, and cancer cells appear to be more sensitive than non-transformed cells to trichostatin A and related HDAC inhibitory compounds. This apparent selectivity of action in cancer cells makes HDAC inhibitors an attractive avenue for drug development. However, in the search for potent HDAC inhibitors with cancer therapeutic potential there has been a tendency to overlook or dismiss weak ligands that could prove effective in cancer prevention, including agents present in the human diet. Recent reports have described butyrate, diallyl disulfide and sulforaphane as HDAC inhibitors, and many other dietary agents will be probably discovered to attenuate HDAC activity. Here we discuss 'pharmacologic' agents that potently de-repress gene expression (e.g. during therapeutic intervention) versus dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important question is the extent to which dietary HDAC inhibitors, and other dietary agents that affect gene expression via chromatin remodeling, modulate the expression of genes such as P21 and BAX so that cells can respond most effectively to external stimuli and toxic insults.
Dashwood
Roderick H
RH
Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331-6512, USA. Rod.Dashwood@oregonstate.edu
Myzak
Melinda C
MC
Ho
Emily
E
D017209:Apoptosis; D002453:Cell Cycle; D018890:Chemoprevention; D042002:Chromatin Assembly and Disassembly; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008024:Ligands
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D006655:Histone Deacetylases