Trichostatin A (TSA)
(Synonyms: 曲古抑菌素A; TSA) 目录号 : GC15526
A potent, reversible inhibitor of histone deacetylases
Cas No.:58880-19-6
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| Cell experiment [1]: | |
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Cell lines |
Human breast cancer cell line |
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Preparation Method |
Trichostatin A (TSA) was added to the cell culture medium. |
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Reaction Conditions |
10 µM of Trichostatin A (TSA) for 96 h |
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Applications |
Trichostatin A (TSA) inhibited the proliferation of 8 breast cancer cell lines, with an average IC50 value of 124.4±120.4 nM. Trichostatin A (TSA) treatment resulted in significant hyperacetylation of histone H4. |
| Animal experiment [2]: | |
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Animal models |
Nmu-induced tumor xenografts of virgin female inbred (Ludwig/Wistar/Olac) rats |
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Preparation Method |
Sixteen animals were injected Trichostatin A (TSA) at a daily dose of 500 microg/kg for 4 weeks |
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Dosage form |
500 µg/kg/day Trichostatin A (TSA), 4 weeks; injected |
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Applications |
Trichostatin A (TSA) had pronounced antitumor activity in vivo when administered to 16 animals at a dose of 500 microg/kg by injection daily for 4 weeks compared with 14 control animals. Furthermore, Trichostatin A (TSA) did not cause any measurable toxicity in doses of up to 5 mg/kg by injection. TSA has significant antitumor activity in vivo The antitumor activity of TSA is attributed to differentiation induction |
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References: [1]: Vigushin DM, Ali S, et,al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res. 2001 Apr;7(4):971-6. PMID: 11309348. |
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Trichostatin A (TSA) is A potent histone deacetylase (HDAC) inhibitor and an antifungal antibiotic with an IC50 value of 1.8 nM for HDAC[1], which has the properties of inhibiting cell growth and inducing cell differentiation.
Trichostatin A (TSA) can arrest cells in G1 and G2 phases, induce cell differentiation, and restore transformed morphology of cultured cells. Trichostatin A (TSA) inhibits proliferation of breast cancer cells in human breast cancer cell linesand resulted in hyperacetylation of histone H4[1]. Trichostatin A (TSA) promotes apoptosis and radiation-induced DNA damage in mitotic G2 gap 2 (G2/M) -arrested cells. Trichostatin A (TSA) may directly participate in DNA damage in esophageal cancer cells by reducing the acetylation of growth-associated genomic protein H3[2].Pre-treatment of RLE-6TN cells with Trichostatin A (TSA) inhibited radiation-induced EMT-like morphological alterations including elevated protein level of α-SMA and Snail, reduction of E-cadherin expression, enhanced phosphorylation of GSK3β and ERK1/2, increased generation of ROS[3].The invasive and migratory abilities of MCF-7 cells were suppressed significantly upon treatment with Trichostatin A (TSA). Treatment with Trichostatin A (TSA) led to an increased expression level of E-cadherin, and decreased expression of vimentin and, in MCF-7 cells[4]. Trichostatin A (TSA) enhanced the radiosensitivity of colon cancer cells, apoptotic cell death induced by radiation was enhanced by Trichostatin A (TSA) treatment. Trichostatin A (TSA) also induced autophagic response in colon cancer cells, while autophagy inhibition led to cell apoptosis and enhanced the radiosensitivity of colon cancer cells[5].
Trichostatin A (TSA) had pronounced antitumor activity in vivo when administered to 16 animals at a dose of 500 microg/kg by injection daily for 4 weeks compared with 14 control animals. Furthermore, Trichostatin A (TSA) did not cause any measurable toxicity in doses of up to 5 mg/kg by injection. Trichostatin A (TSA) has significant antitumor activity in vivo The antitumor activity of Trichostatin A (TSA) is attributed to differentiation induction[1].In porcine SCNT embryos,Chaetocin, Trichostatin A (TSA), and the combination significantly increased the cleavage and blastocyst formation rate, hatching/hatched blastocyst rate, and cell numbers and survival rate. The combined treatment improved the rate of development to blastocysts more so than chaetocin or Trichostatin A (TSA) alone[6].This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with Trichostatin A (TSA) 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. HDAC inhibitor Trichostatin A (TSA) may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress[7].
References:
[1]: Vigushin DM, Ali S, et,al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res. 2001 Apr;7(4):971-6. PMID: 11309348.
[2]: Wang S, Song M, et,al. Trichostatin A enhances radiosensitivity and radiation-induced DNA damage of esophageal cancer cells. J Gastrointest Oncol. 2021 Oct;12(5):1985-1995. doi: 10.21037/jgo-21-560. PMID: 34790366; PMCID: PMC8576220.
[3]: Nagarajan D, Wang L, et,al. Trichostatin A inhibits radiation-induced epithelial-to-mesenchymal transition in the alveolar epithelial cells. Oncotarget. 2017 Oct 9;8(60):101745-101759. doi: 10.18632/oncotarget.21664. PMID: 29254201; PMCID: PMC5731911.
[4]: Wang X, Chen S, et,al. Trichostatin A reverses epithelial-mesenchymal transition and attenuates invasion and migration in MCF-7 breast cancer cells. Exp Ther Med. 2020 Mar;19(3):1687-1694. doi: 10.3892/etm.2020.8422. Epub 2020 Jan 3. PMID: 32104221; PMCID: PMC7027139.
[5]: He G, Wang Y, et,al. Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation. Tumour Biol. 2014 Feb;35(2):1003-11. doi: 10.1007/s13277-013-1134-z. PMID: 24122231.
[6]: Jeong PS, Yang HJ, et,al. Combined Chaetocin/Trichostatin A Treatment Improves the Epigenetic Modification and Developmental Competence of Porcine Somatic Cell Nuclear Transfer Embryos. Front Cell Dev Biol. 2021 Oct 6;9:709574. doi: 10.3389/fcell.2021.709574. PMID: 34692674; PMCID: PMC8526721.
[7]: Kimijima H, Miyagawa K, et,al. Trichostatin A, a histone deacetylase inhibitor, alleviates the emotional abnormality induced by maladaptation to stress in mice. Neurosci Lett. 2022 Jan 1;766:136340. doi: 10.1016/j.neulet.2021.136340. Epub 2021 Nov 10. PMID: 34774702.
Trichostatin A (TSA) 是一种有效的组蛋白脱乙酰酶 (HDAC) 抑制剂和抗真菌抗生素，对 HDAC[1] 的 IC50 值为 1.8 nM，具有抑制细胞生长和诱导细胞分化。
曲古抑菌素 A (TSA) 可以将细胞阻滞在 G1 和 G2 期，诱导细胞分化，并恢复培养细胞的转化形态。曲古抑菌素 A (TSA) 抑制人乳腺癌细胞系中乳腺癌细胞的增殖，并导致组蛋白 H4 过度乙酰化[1]。曲古抑菌素 A (TSA) 促进有丝分裂 G2 间隙 2 (G2/M) 阻滞细胞的细胞凋亡和辐射诱导的 DNA 损伤。曲古抑菌素A（TSA）可能通过降低生长相关基因组蛋白H3[2]的乙酰化水平直接参与食管癌细胞DNA损伤。曲古抑菌素A（TSA）预处理RLE-6TN细胞) 抑制辐射诱导的 EMT 样形态学改变，包括 α-SMA 和 Snail 蛋白水平升高、E-钙粘蛋白表达降低、GSK3β 和 ERK1/2 磷酸化增强、ROS 生成增加[3].MCF-7 细胞的侵袭和迁移能力在用曲古抑菌素 A (TSA) 处理后被显着抑制。在 MCF-7 细胞中用曲古抑菌素 A (TSA) 处理会导致 E-cadherin 表达水平升高，波形蛋白和 vimentin 表达降低[4]。曲古抑菌素A (TSA) 增强了结肠癌细胞的放射敏感性，曲古抑菌素A (TSA) 处理增强了辐射诱导的凋亡细胞死亡。曲古抑菌素A（TSA）也诱导结肠癌细胞自噬反应，抑制自噬导致细胞凋亡，增强结肠癌细胞的放射敏感性[5]。
与 14 只对照动物相比，通过每天注射 500 微克/公斤的剂量给 16 只动物给药 4 周，曲古抑菌素 A (TSA) 在体内具有显着的抗肿瘤活性。此外，曲古抑菌素 A (TSA) 在高达 5 mg/kg 的注射剂量下未引起任何可测量的毒性。 Trichostatin A (TSA) 在体内具有显着的抗肿瘤活性 Trichostatin A (TSA) 的抗肿瘤活性归因于分化诱导[1]。在猪SCNT 胚胎中，Chaetocin、Trichostatin A (TSA) 和该组合显着提高了卵裂和囊胚形成率、孵化/孵化囊胚率以及细胞数量和存活率。与单独使用毛壳菌素或曲古抑菌素 A (TSA) 相比，联合治疗更能提高胚泡的发育速度[6]。在应激适应不良小鼠中观察到的这种情绪下降通过曲古抑菌素 A 的长期治疗显着恢复(TSA) 每天暴露于束缚压力前 2 小时，这证实了压力适应的发展。 HDAC 抑制剂曲古抑菌素 A (TSA) 可能通过影响大脑中的 5-HT 神经功能对应激适应产生有益作用，并减轻过度应激条件下的情绪异常[7]。
| Cas No. | 58880-19-6 | SDF | |
| 别名 | 曲古抑菌素A; TSA | ||
| 化学名 | (2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide | ||
| Canonical SMILES | CC(C=C(C)C=CC(=O)NO)C(=O)C1=CC=C(C=C1)N(C)C | ||
| 分子式 | C17H22N2O3 | 分子量 | 302.37 |
| 溶解度 | ≥ 15.12mg/mL in DMSO, ≥ 16.56 mg/mL in EtOH with ultrasonic | 储存条件 | Desiccate at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3072 mL | 16.536 mL | 33.0721 mL |
| 5 mM | 0.6614 mL | 3.3072 mL | 6.6144 mL |
| 10 mM | 0.3307 mL | 1.6536 mL | 3.3072 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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HDAC inhibitor Trichostatin A suppresses adipogenesis in 3T3-L1 preadipocytes
Background and purpose: Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism. Methods: The adipogenesis of 3T3-L1 cells was induced by stimulation with a differentiation cocktail (DMI) medium for 8 days. MTT assay was used to measure the cell viability and Oil Red O staining was used to evaluate the adipogenesis of 3T3-L1 cells. The total level of triglyceride and released glycerol were detected to evaluate the lipolysis during 3T3-L1 adipogenesis. The expression levels of Leptin, fatty acid-binding protein 4 (FABP4), and sterol regulatory element-binding protein (SREBP1C) were determined by qRT-PCR. qRT-PCR assay was utilized to detect the expression levels of PPARγ and C/EBPα in 3T3-L1 cells. A high-fat diet (HFD) was used to construct an obese mice model, followed by the treatment with TSA. HE staining was conducted to evaluate the pathological state of adipose tissues. Body weights and the weights of adipose tissues were recorded to evaluate the anti-obesity property of TSA. Results: Firstly, the promoted lipid accumulation induced by DMI incubation was significantly reversed by the treatment with TSA in a dose-dependent manner. The elevated expression levels of Leptin, FABP4, SREBP1C, PPARγ, and C/EBPα induced by the stimulation with DMI incubation were dramatically inhibited by the introduction of TSA, accompanied by the upregulation of phosphorylated AMP-activated protein kinase (p-AMPK). Secondly, the inhibitory effect of TSA against the expression level of PPARγ and lipid accumulation was greatly abolished by an AMPK inhibitor. Lastly, the increased body weights and visceral adipocyte tissue weight, as well as the enlarged size of adipocytes induced by HFD were pronouncedly reversed by the administration of TSA. Conclusion: TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.
Trichostatin A ameliorates Alzheimer's disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice
Background: Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.
Methods: Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.
Results: TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers.
Conclusions: These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Sex- and OGG1-dependent reversal of in utero ethanol-initiated changes in postnatal behaviour by neonatal treatment with the histone deacetylase inhibitor trichostatin A (TSA) in oxoguanine glycosylase 1 (Ogg1) knockout mice
Oxoguanine glycosylase 1 (OGG1) is both a DNA repair enzyme and an epigenetic modifier. We assessed behavioural abnormalities in OGG1-deficient progeny exposed once in utero to a low dose of ethanol (EtOH) and treated postnatally with a global histone deacetylase inhibitor, trichostatin A (TSA). The goal of this study was to determine if neurodevelopmental disorders initiated in the fetal brain by in utero exposure to EtOH could be mitigated by postnatal treatment with TSA. EtOH and TSA alone improved preference for novel location (short-term, 90 min) and novel object (long-term, 24 h) sex- and OGG1-dependently. Combined EtOH/TSA treatment reversed these effects in the short-term novel location test sex- and OGG1-dependently. In females but not males, the incidence of high shredders of nesting material was not altered by either TSA or EtOH alone, but was reduced by combined EtOH/TSA treatment in +/+ progeny. Similar but non-significant effects were observed in Ogg1 -/- females. Accelerated rotarod performance was enhanced by both EtOH and TSA alone in only male Ogg1 +/+ but not -/- progeny, and was not altered by combined EtOH/TSA exposure. The OGG1-dependent effects of EtOH and TSA particularly on novel location and the incidence of high shredders, and the reversal of EtOH effects on these parameters by combined EtOH/TSA treatment, suggests both xenobiotics may alter behaviour via a mechanism involving OGG1 acting as an epigenetic modifier, in addition to repairing DNA damage. These preliminary results suggest that the postnatal use of more selective epigenetic modifying agents may constitute a novel strategy for mitigating some components of ROS-initiated neurodevelopmental disorders.
Trichostatin A (TSA) facilitates formation of partner preference in male prairie voles (Microtus ochrogaster)
In the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a receptor (V1aR) genes expression in the nucleus accumbens (NAcc). In the present study, we tested the hypothesis that TSA treatment also facilitates partner preference formation and alters OTR and V1aR genes expression in the NAcc in male prairie voles. We thus observed that central injection of TSA dose-dependently promoted the formation of partner preference in the absence of mating in male prairie voles. Interestingly, TSA treatment up-regulated OTR, but not V1aR, gene expression in the NAcc similarly as they were affected by mating - an essential process for naturally occurring partner preference. These data, together with others, not only indicate the involvement of epigenetic events but also the potential role of NAcc oxytocin in the regulation of partner preference in both male and female prairie voles.
Differential effects of trichostatin A on mouse embryogenesis and development
Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, can significantly improve the reprogramming efficiency of somatic cells. However, whether TSA has a detrimental effect on other kinds of embryos is largely unknown because of the lack of integrated analysis of the TSA effect on natural fertilized embryos. To investigate the effect of TSA on mouse embryo development, we analyzed preimplantation and post-implantation development of in vivo, in vitro fertilized, and parthenogenetic embryos treated with TSA at different concentrations and durations. In vivo fertilized embryos appeared to be the most sensitive to TSA treatment among the three groups, and the blastocyst formation rate decreased sharply as TSA concentration and treatment time increased. TSA treatment also reduced the livebirth rate for in vivo fertilized embryos from 56.59 to 38.33% but did not significantly affect postnatal biological functions such as the pups' reproductive performance and their ability for spatial learning and memory. Further analysis indicated that the acetylation level of H3K9 and H4K5 was enhanced by TSA treatment at low concentrations, while DNA methylation appeared to be also disturbed by TSA treatment only at high concentration. Thus, our data indicates that TSA has different effects on preimplantation embryonic development depending on the nature of the embryo's reproductive origin, the TSA concentration and treatment time, whereas the effect of TSA at the indicated concentration on postnatal function was minor.