Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells

Abstract

Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. One class of HDAC inhibitors, hydroxamic acid-based hybrid polar compounds (HPCs), induce differentiation at micromolar or lower concentrations. Studies (x-ray crystallographic) showed that the catalytic site of HDAC has a tubular structure with a zinc atom at its base and that these HDAC inhibitors, such as suberoylanilide hydroxamic acid and trichostatin A, fit into this structure with the hydroxamic moiety of the inhibitor binding to the zinc. HDAC inhibitors cause acetylated histones to accumulate in both tumor and normal tissues, and this accumulation can be used as a marker of the biologic activity of the HDAC inhibitors. Hydroxamic acid-based HPCs act selectively to inhibit tumor cell growth at levels that have little or no toxicity for normal cells. These compounds also act selectively on gene expression, altering the expression of only about 2% of the genes expressed in cultured tumor cells. In general, chromatin fractions enriched in actively transcribed genes are also enriched in highly acetylated core histones, whereas silent genes are associated with nucleosomes with a low level of acetylation. However, HDACs can also acetylate proteins other than histones in nucleosomes. The role that these other targets play in the induction of cell growth arrest, differentiation, and/or apoptotic cell death has not been determined. Our working hypothesis is that inhibition of HDAC activity leads to the modulation of expression of a specific set of genes that, in turn, result in growth arrest, differentiation, and/or apoptotic cell death. The hydroxamic acid-based HPCs are potentially effective agents for cancer therapy and, possibly, cancer chemoprevention.

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

“…Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. [5] Several such inhibitory agents, including suberoyanilide hydroxamic acid (SAHA, aka virinostat) and depsipeptide (FR901228) have reached clinical trials, [6][7][8] and SAHA has been approved by the FDA for use in cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors (HDACIs) also enhance the cytotoxic effects of both radiation and chemotherapeutic drugs.…”

Modulation of cellular radiation responses by histone deacetylase inhibitors

“…This results in neutralization of the positive charges on histones and decreases their interaction with the negatively charged DNA. The effect is a 'relaxed' or more open, transcriptionally active, chromatin conformation (Marks et al, 2000). The HDACs catalyse the removal of acetyl groups from lysine residues resulting in a more compacted, transcriptionally repressed, chromatin structure (Marks et al, 2001).…”

Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis

“…They increase transcription activity by altering chromatin structure, but interestingly they activate transcription of selected genes and cause terminal differentiation, cell-cycle arrest or apoptosis in a variety of cancer cells. [2][3][4][5][6] Since the antiproliferative and proapoptotic activity is somehow restricted to transformed cells, HDAC inhibitors are promising new class of anticancer agents against a broad range of hematologic and solid tumors. 7 So far Phase I clinical trials with an HDAC inhibitor the depsipeptide FK228 are encouraging and Phase II trials have been initiated in cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck.…”