A review of Histone Deacetylase inhibitors and their application in veterinary medicine

Abstract

The role of epigenetic determinants in regulating cellular processes and functions of living organisms has become increasingly clear. Although the environment clearly has an influence on the epigenetic landscape, there are only a few tools to interfere in a controlled manner with the histone modification pattern. However, histone deacetylase inhibitors represent such a tool. In recent years a large number of studies were conducted on histone deacetylase (HDAC) inhibitors and the role of histone acetylation in cellular processes. The knowledge of the structure of DNA and chromatin is fundamental for the comprehension of the mechanism of action of the HDAC inhibitors. Nucleosomes made up of DNA wrapped around a core of eight histones, form the key structural units of chromatin that are essential for the packing of eukaryotic DNA. The long N-terminal extensions of these histones undergo many posttranslational modifications such as acetylation, methylation, phosphorylation and ubiquitination. It is only in the past decade or so that the scientific community has established the role of posttranslational modifications in the epigenetic regulation of DNA. In the 1990’s, the first of the enzymes responsible for the deacetylation of histone tails of chromatin were identified. Histone deacetylases (HDACs) are a class of enzymes found in bacteria, fungi, plants and animals that remove the acetyl group from the ε-amino groups of lysine residues located in the N-terminal tails of core histones. Histone deacetylases (HDAC’s) and their counterparts the histone acetyl transferases (HAT’s) are two opposing enzyme families responsible for controlling the acetylation status of chromatin. In this way, they play a crucial role in chromatin remodelling and in the regulation of gene transcription. While the HAT’s add acetyl groups onto lysine residues on histone tails, the HDAC’s remove them. Acetylation of the ε-amino group of lysine residues neutralizes their positive charge and prevents the histone tails interacting with the negatively charged DNA. This gives rise to a relaxed chromatin structure, thus allowing transcriptional activation. Conversely, deacetylation by the HDAC’s acts as a method of transcription repression by condensing the chromatin. Histone deacetylase inhibitors (HDAC inhibitors) are emerging as a new class of drug candidates, in particular in antineoplastic therapy and have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo. In October 2006 the FDA approved the first HDAC inhibitor – Vorinostat (Zolinza, Suberoylanilide hydroxamic acid, formerly known as SAHA) to treat the rare cancer cutaneous T-cell lymphoma (CTCL). At least 12 different HDACIs are currently in some phase of clinical trials as monotherapy or in combination chemotherapy or radiation therapy in patients with hematologic and solid tumors, including lung, breast, pancreas, renal, and bladder cancers, melanoma, glioblastoma, leukaemia’s, lymphomas, and multiple myeloma. HDAC inhibitors are also being investigated for the treatment of neurodegenerative and psychiatric disorders and inflammation. In the final chapter, the application of HDAC inhibitors in a number of areas was examined, namely: antineoplastic therapy, inflammation, Cushing’s disease and their use as feed additives. These topics were chosen specifically due to their relevance in veterinary medicine. Of the neoplastic conditions, canine haemangiosarcoma is currently the most studied with regards to the use of HDAC inhibitors and drug development is at a quite advanced stage. A number of HDAC inhibitors have also emerged as promising anti-inflammatory agents. In canine and equine medicine, an alternative to current medical therapy of arthritis and other degenerative joint diseases would be greatly welcomed. The Utrecht study of Cushing’s disease revealed the role of HDAC’s in glucocorticoid repression of transcription of the POMC gene. HDAC inhibitors were found to prevent the sensitivity of POMC transcription to glucocorticoids. Butyrate was found to be a successful alternative to antibiotics as a feed additive in a number of studies with piglets, calves and poultry. However, until there is a greater understanding of epigenetics and the role of HDAC’s and HDAC inhibitors in animal diseases, progress in veterinary medicine will continue to depend on the advances in human medicine.