“The inhibition of HDACs cause growth arrest, terminal differentiation or death of a broad spectrum of tumor cells in vitro, as well as, in tumor bearing animals.”

The paper was one of the first comprehensive reviews of the discovery and development of histone deacetylase inhibitors (HDACi) as anti-cancer drugs. HDACi represent a new, targeted approach to cancer therapy. The HDACi, such as hydroxamic acid-based suberoylanilide hydroxamide (SAHA), are effective at sub-micromolar concentrations causing growth arrest of a broad spectrum of cancer cells in culture, as well as of tumor growth in cancer-bearing animals. SAHA is in phase I/II clinical trials and has demonstrated significant anti-cancer activity against hematologic and solid tumors at doses well tolerated by patients. This paper reviews studies on the mechanism of action of HDACi including their targets, histone deacetylases, which lead to the accumulation of acetylated histones and altered chromatin structure. Histone deacetylases play a role in determining the state of acetylation and activity of other proteins including some critical in regulation in cell cycle progression, mitosis, and cytokinesis. HDACi are selective in the genes whose expression is altered and normal cells are much more resistant than transformed cells to these agents.

Our own research goes back to the mid 1970s, when we discovered that a group of hybrid polar compounds, such as hexamethylene bisacetamide, were effective in inducing cell growth arrest, terminal differentiation, and/or apoptosis of transformed cells in culture. Over the years we discovered histone deacetylase inhibitors, of which SAHA is the prototype, that are 1,000-fold more potent than hexamethylene bisacetamide in causing growth arrest of transformed cells. We gained an understanding of the mechanism of action of these agents, and developed lead compounds that are in clinical trials in patients with cancers.

Deoxyribonucleic acid (DNA) contains the basic code determining characteristics of cells. The expression of the genes that are coded in DNA is largely regulated by the structure of proteins around which the DNA is wrapped in chromatin, namely so-called epigenetic modulation of gene expression. One of the most-studied modifications of proteins regulating the expression of genes is the acetylation and deacetylation of histone proteins, which make up the core of the chromatin. The state of acetylation of these histone proteins is determined by the activity of two classes of enzymes, namely histone acetyl transferases (HATs) and histone deacetylases (HDACs). It is known that alterations in the structure and/or function of HATs and HDACs are common abnormalities in many cancer cells.

Recently, a number of small molecule inhibitors of the enzyme activity of HDACs have been discovered and characterized. The inhibition of HDACs causes growth arrest, terminal differentiation, or death of a broad spectrum of tumor cells in vitro, as well as in tumor-bearing animals. Histone deacetylase inhibitors are now being exploited as possible novel approaches to the treatment of cancers. Indeed, as mentioned, a lead compound, SAHA, is in Phase I/II clinical trials and has shown that it can be orally administered and has demonstrated significant activity against both hematological and solid tumors at doses that are well tolerated. These agents are selective in the genes whose transcription is altered and in effects on cancer cells as compared to normal cells. The basis of the selectivity of these HDAC inhibitors for cancer cells is not yet well understood. Further understanding of the mechanism of action of these agents will lead to a better understanding of the process of transformation of normal to cancer cells and to the development of new, well-tolerated anti-cancer agents.

Paul A. Marks, M.D.
President Emeritus, Memorial Sloan Kettering Cancer Center
New York, NY, USA