Histone deacetylase as a new target for cancer chemotherapy

Abstract

Trichostatin A (TSA) and trapoxin (TPX), inhibitors of the eukaryotic cell cycle and inducers of morphological reversion of transformed cells, inhibit histone deacetylase (HDAC) at nanomolar concentrations. Recently, FK228 (also known as FR901228 and depsipeptide) and MS-275. antitumor agents structurally unrelated to TSA, have been shown to be potent HDAC inhibitors. These inhibitors activate the expression of p21Waf1 in a p53-independent manner. Changes in the expression of regulators of the cell cycle, differentiation, and apoptosis with increased histone acetylation may be responsible for the cell cycle arrest and antitumor activity of HDAC inhibitors. TSA has been suggested to block the catalytic reaction by chelating a zinc ion in the active site pocket through its hydroxamic acid group. On the other hand, an epoxyketone has been suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound, called cyclic hydroxamic-acid-containing peptide 1 (CHAP1) inhibited HDAC at low nanomolar concentrations. The HDAC1 inhibition by CHAPI was reversible, as is that by TSA, in contrast to irreversible inhibition by TPX. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, while TSA inhibited these HDACs to a similar degree. CHAP31, the strongest HDAC inhibitor obtained from a variety of CHAP derivatives, exhibited antitumor activity in BDF1 mice bearing B16/BL6 tumor cells. These results suggest that CHAP31 is promising as a novel therapeutic agent for cancer treatment, and that CHAP may serve as a basis for new HDAC inhibitors and be useful for combinatorial synthesis and high-throughput screening.

Subtype Selective Substrates for Histone Deacetylases

“…This would be much easier than using immunoprecipitated subtypes and a nonselective substrate. We compared the subtype selectivities of two TSA-like inhibitors 17 M344 (16b) and M360 (16c) and three structurally unrelated cyclotetrapeptide inhibitors (CHAPs 18,19 ) ( Figure 4). M344 (16b) was selective for HDAC6 vs HDAC1 (IC 50 , 88 vs 249 nM).…”

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

“…Acetylation neutralizes the charge of the histones and generates a more open DNA conformation. Since aberrant histone acetylation has been linked to malignant diseases in some cases, HDAC inhibitors (HDIs) have potential as new drugs due to their ability to modulate transcription and to induce differentiation and apoptosis (5). Molecular analyses of human diseases have suggested that changes in acetylation may play a role in the uncontrolled cell growth of cancer.…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…[3][4][5][6][7][8][9] HDACIs also induce cell cycle arrest at the G 1 and/or G 2 /M phases of the cell cycle, cause differentiation and/or apoptosis, and exhibit potent anti-tumor activity against a variety of tumor cells, both in vitro and in vivo. [1][2][3][4][5][6][7][8] In addition, HDACIs have the advantage of being less toxic in normal cells than in cancer cells. [10][11][12][13][14] Based on their pleiotropic cellular effects and their tumor-selectivity, several HDACIs are currently undergoing clinical trials, and some of them have shown promising anti-tumor activity.…”

“…Modulating gene expression by using HDACIs may therefore represent a significantly more powerful approach to treat cancer than the targeting of a single genetic pathway. [3][4][5][6][7][8] HDACIs treatments have been shown to cause hyperacetylation of nucleosomal histones of condensed chromatin, and thus, to effect the reactivation of silenced genes. [3][4][5][6][7][8][9] HDACIs also induce cell cycle arrest at the G 1 and/or G 2 /M phases of the cell cycle, cause differentiation and/or apoptosis, and exhibit potent anti-tumor activity against a variety of tumor cells, both in vitro and in vivo.…”

“…[3][4][5][6][7][8] HDACIs treatments have been shown to cause hyperacetylation of nucleosomal histones of condensed chromatin, and thus, to effect the reactivation of silenced genes. [3][4][5][6][7][8][9] HDACIs also induce cell cycle arrest at the G 1 and/or G 2 /M phases of the cell cycle, cause differentiation and/or apoptosis, and exhibit potent anti-tumor activity against a variety of tumor cells, both in vitro and in vivo. [1][2][3][4][5][6][7][8] In addition, HDACIs have the advantage of being less toxic in normal cells than in cancer cells.…”