HDAC inhibitors for cancer chemoprevention

The treatment of several diseases is highly dependent on natural products and this is especially true in the case of cancer. Most of human cancers seems to be potentially avoidable by controlling exogenous factors (primary prevention), but also by using agents interfering with carcinogenesis. These compounds can be divided into three categories: blocking agents (anti-initiation), agents against the promotion or the progression stages. Epigenetic changes, induced by compounds acting on the methylation or acetylation status of the histones, mostly act in the last stage.

Histone deacetylases (HDACs) are enzymes that deacetylate lysine residues from histones, as well as several other nuclear, cytoplasmic or mitochondrial proteins. In mammals, there are 11 zinc-dependent HDACs classified in three classes: class I (HDACs 1 – 3 and HDAC8), class II which is subdivided into classes IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6 and 10), and class IV (HDAC11). During the past years, the number of enzyme subtypes has increased and offers the possibility to develop HDAC inhibitors with increased specificity. In the case of cancer, these specific inhibitors should have a better efficacy and decreased side effects. A method using mass spectrometry was developed to measure the inhibitory activity against classes I and II isoforms in a single sample. Various diterpenes and aurones showed promising results and will be discussed. The use of epigenetic modulators could be an optimal intervention to prevent early epigenetic changes and decrease the prevalence of age-related diseases such as cancer.