生物活性

• 靶点	HDAC IC50:~1.8nM

• 描述HDACs are a group of enzymes that remove acetyl groups and regulate the histone tail, protein-DNA interaction, chromatin conformation, and even transcription. There are 18 mammalian HDACs divided into four classes: class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), class III (sirtuin family: sirt1-sirt7) and class IV (HDAC11)^[1]. Trichostatin A (TSA) is the inhibitors of the class I and class II HDACs with IC50 value of 2.4 ± 0.5 nM (measured by HDAC activity in cellular extracts). Trichostatin A treatment with concentration of 2 μM for 24h can increase histone H4 hyperacetylation in all of the breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, and SK-BR-3) significantly and inhibit the cell growth with IC50 values ranging in 26 – 308 nM in 96h. Treatment of 500 μg/kg trichostatin A by s.c injection daily for 4 weeks significantly inhibited tumor growth in Ludwig/Wistar/Olac female rats bearing tumors induced with NMU, compared with control^[2]. Trichostatin A is usually used in the study of tumor growth inhibition. The cell death and cell cycle arrest induced by it may involve in several mechanisms including transcription-dependence and -independence, such as cell cycle arrest, apoptosis, the regulation of ROS and the inhibition of angiogenesis^[3].
• 作用机制Trichostatin A comprises a hydroxamic acid-based metal-binding domain that coordinates the catalytic Zn(II) in the HDAC active site^[4].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780	0.05-2 μM	Growth Inhibition Assay	10/24/48 h	mediates growth arrest in a concentration- and time-dependent manner	24223801
  A431	2/10/50/100nM	Apoptosis Assay	48h	inhibits the cell growth	25371069
  A431	50nM	Function Assay	2/6/12/24h	activates p21 and inhibits ATF3 expression	25371069

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• 动物研究
  剂量	Mice[5] (i.p.): min = 0.5 mg/kg, max = 80 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[5] Dose 80 mg/kg Administration i.p. Cmax 40 μg/ml Tmax 3.5 min

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03049124	Rectal Cancer	Not Applicable	Recruiting	July 31, 2019	Canada, Ontario ... more >> University of Ottawa Recruiting Ottawa, Ontario, Canada, K1N 6N5 Contact: Amanda Wurz, MSc    613-562-5800 ext 3626    amanda.wurz@uottawa.ca Collapse <<
  NCT02152267	Craniomandibular Disorders	Not Applicable	Completed	-	Brazil ... more >> Federal University of Bahia Salvador, Bahia, Brazil, 40110-902 Collapse <<
  NCT01028014	Urethral Sphincter Activity	Not Applicable	Completed	-	United States, Alabama ... more >> University of Alabama at Birmingham, The Kirklin Clinic Birmingham, Alabama, United States, 35233 Collapse <<

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• 参考文献

• [1] Yoon S, Eom GH, et al. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med J. 2016 Jan;52(1):1-11.

  [2] 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.

  [3] Xu WS, Parmigiani RB, et al. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52.

  [4] Codd R, Braich N, et al. Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol. 2009 Apr;41(4):736-9.

  [5] Sanderson L, Taylor GW, et al. Plasma pharmacokinetics and metabolism of the histone deacetylase inhibitor trichostatin a after intraperitoneal administration to mice. Drug Metab Dispos. 2004 Oct;32(10):1132-8. Epub 2004 Jul 21.

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