Background
Tubastatin A is a potent and selective inhibitor of HDAC6 with IC50 value of 15 nM [1].
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) mediates the balance between histone deacetylation and acetylation. HDACs also regulate the acetylation status of signaling molecules, chaperones, and transcription factors that are non-histone proteins [2]. HDAC6 interacts with the HSP90 which is a molecular chaperone. The deacetylation of HSP90 by HDAC6 is important for the stability and of many client proteins including Bcr-Abl, c-Raf, and AKT. So, HDAC inhibitors have anti-cancer function [2].
Tubastatin A is a selective inhibitor of HDAC6 compared with other HDACs. Tubastatin A maintained an average 200-fold selectivity compared with class I HDACs. Tubastatin A displayed selectivity against all isoforms excluding HDAC8 over 1000-fold.
Tubastatin A protected against HCA induced neuronal cell death in a dose-dependent manner. Tubastatin A induced the hyperacetylation of? α-tubulin at 2.5 μM[1]. In LPS stimulated human THP-1 macrophages, Tubastatin A displayed significant inhibition of IL-6 and TNF with an IC50 of 712 nM and 212 nM [3]. Tubastatin A showed the inhibition of nitric oxide (NO) secretion with an IC50 of 4.2μM in murine Raw 264.7 macrophages [3]. Tubastatin-A also significantly inhibit cell proliferation at 10μM in KMCH cells [4].
Tubastatin A showed inhibition of paw volume at 30 mg/kg in an animal model of inflammation[3]. Tubastatin-A treatment reduced tumor growth and induces ciliogenesis in rat orthotopic model of cholangiocarcinoma at 10 mg/kg [4].
参考文献:
1.Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP: Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 2010, 132(31):10842-10846.
2.Kim HJ, Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res 2011, 3(2):166-179.
3.Vishwakarma S, Iyer LR, Muley M, Singh PK, Shastry A, Saxena A, Kulathingal J, Vijaykanth G, Raghul J, Rajesh N et al: Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int Immunopharmacol 2013, 16(1):72-78.
4.Gradilone SA, Radtke BN, Bogert PS, Huang BQ, Gajdos GB, LaRusso NF: HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res 2013, 73(7):2259-2270.
Protocol
| Cell experiment [1]: |
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Cell lines
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Human breast cancer cells (MCF-7).
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Preparation method
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Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reaction Conditions
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15, 30 μM; 48 h.
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Applications
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In MCF-7 cells, tubastatin A inhibits cell proliferation in a dose-dependent way with IC50 value of 15 μM and increases the acetylation of cytoplasmic microtubules. Also, tubastatin A reduces the microtubule depolymerization rate induced by cold and 200 nM nocodazole, which is mediated by the inhibition of HDAC6.
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| Animal experiment [2]: |
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Animal models
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Wistar rats; DBA1 mice
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Dosage form
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Rats: 30 mg/kg/day i.p. for 5 days; mice: 30 mg/kg, q.d. from day 21 to day 36.
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Preparation method
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Solubilized in 10% Dimethyl sulfoxide (DMSO) 10% Polyethylene glycol (PEG) 400 and 80% (40% of hydroxy propyl beta cyclodextrin).
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Applications
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In FCA injected rats, tubastatin significantly reduces paw volume by 71.9% at 2 h. In DBA1 arthritis mouse induced by semi-therapeutic collagen, tubastatin (30 mg/kg/day, i.p.) significantly reduces arthritic clinical scores by 73% and inhibits the production of IL-6 in paw tissues by 59%. Tubastatin treated mice shows insignificant changes in body weight.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Asthana J, Kapoor S, Mohan R, et al. Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells. J Biol Chem, 2013, 288(31): 22516-22526.
[2]. Vishwakarma S, Iyer LR, Muley M, et al. Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int Immunopharmacol, 2013, 16(1): 72-78.
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