Structural specificity for biological activity of trichostatin a, a specific inhibitor of mammalian cell cycle with potent differentiation-inducing activity in friend leukemia cells.

Abstract

Biologicalactivities of four chemically synthesized trichostatin-related compounds, (R)-trichostatin A, (S)-trichostatin A, (It )-trichostatic acid, and (S)-trichostatic acid, were investigated. Assays of differentiation-inducing activity in Friend leukemia cells and G2-arresting activity in the cell cycle of normal rat fibroblast cells were used as monitoring systems for comparing the bioactivities of these compounds.The results clearly showedthat both of the enantiomers of trichostatic acid had no activity in both the assay systems. In the case of (S)-trichostatin A, the antipode of naturally occurring trichostatin A, 50% effective concentrations were determined to be 50~70-fold higher than those of (R )-trichostatin A. The relationship between this ratio and the value of enantiomeric excess strongly suggests that (5)-trichostatin A is also biologically inactive. These results indicate that the absolute configuration and the presence of the hydroxamate group of trichostatin A are essential for its biological activity. TrichostatinsA and C (Fig. 1), which had been originally discovered as fungistatic antibiotics by Tsuji et ah, Tsuji and Kobayashi1 2), were also found by our group to be very potent inducers of erythroid differentiation in mouse Friend leukemia cells3>4). More interestingly, we found that a low concentration of trichostatin A reversibly blocked the cell cycle of normal fibroblast cells at both the G! and G2 phases and induced the formation of proliferative tetraploid cells after release from the G2-arrest by this drug5). These observations suggest that trichostatin A will be useful for studying the mechanisms of cell differentiation and the eukaryotic cell cycle.MORIOKA et ah reported independently that trichostatic acid (Fig. 1) showed a similar effect on Friend leukemia cells, although its effective concentration was about 1,000-fold higher than that of trichostatin A6). Recently, they have also reported that the racemic form of trichostatic acid had no activity as a differentiation inducer7). To verify these observations and the relationship of stereochemistry to biological activity, MORI and Koseki synthesized both enantiomers of trichostatin A and trichostatic acid8). In this paper, we compared their biological activities, and concluded that (i^-trichostatin A, a naturally occurring substance, was the only active agent among these four compounds. Materials and Methods Chemicals and Physico-chemical MeasurementsPurified preparations of (R )-trichostatin A ( > 93% enantiomeric excess), (S)-trichostatin A ( >93 % enantiomeric excess), (i? )-trichostatic acid (98 %

Efficacy on anaplastic thyroid carcinoma of valproic acid alone or in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative, or lactacystin

“…HDAC inhibitors (HDACIs) inhibit malignant cell growth in vitro and in vivo to bring about the reversion of oncogenetransformed cell morphology (4) and to induce apoptosis (5). Several classes of HDACIs have been identified; these include organic hydroxamic acids such as trichostatin A (TSA) and suberoyl anilide bishydroxamine (SAHA), short-chain fatty acids such as butyrates and valproic acid (VPA), cyclic tetrapeptides (e.g., trapoxin), and benzamides (e.g., MS-275) (6).…”

Sodium Butyrate Inhibits the Self-Renewal Capacity of Endometrial Tumor Side-Population Cells by Inducing a DNA Damage Response

“…HDACi's include short-chain fatty acids (e.g., butyrates and valporic acid), organic hydroxamic acids [trichostatin A and suberoyl anilide bishydroxamine (SAHA)], cyclic tetra peptides (e.g., trapoxin), and bezamides (e.g., MS-275). Trichostatin A, NaB, valporic acid, and SAHA can inhibit malignant cells in vitro and in vivo (37)(38)(39). We have previously shown that NaB induced p21 expression, resulting in growth arrest and cell death (34).…”

Histone deacetylase inhibitors induce growth inhibition, cell cycle arrest and apoptosis in human choriocarcinoma cells

“…HDAC inhibitors (HDACIs) such as trichostatin A (TSA) and sodium butyrate (NaB) can inhibit cancer cell growth in vitro (9) and in vivo (10), revert oncogene-transformed cell morphology (11), induce apoptosis (12), and enhance cell differentiation (13). Several classes of HDACIs have been identified, including: a) short-chain fatty acids [e.g., butyrates and valproic acid (VPA)]; b) organic hydroxamic acids [e.g., TSA and suberoyl anilide bishydroxamine (SAHA)]; c) cyclic tetrapeptides (e.g., trapoxin); and d) benzamides (e.g., MS-275) (14).…”