A class I HDAC inhibitor
Valproic acid is an inhibitor of HDAC1 with IC50 value of 0.4mM [1].
Valproic acid (VPA) is a branched short-chain fatty acid. It is previously synthesized and used as an inert solvent of organic compounds. VPA is then found to have ability in preventing pentylenetetrazol-induced convulsions in rodents. It is used as an antiepileptic drug via inhibiting the activity of GABA. VPA is found to inhibit the degradation of GABA and increase GABA synthesis as well as inhibit GABA Transaminobutyratre. It also blocks Na+ channels, Ca2+ channels and voltage-gated K+ channels. Besides that, VPA is reported as an inhibitor of HDAC, making it to be a potential therapeutic for cancers. VPA inhibits HDAC1 in vitro with IC50 value of 0.4mM. For nuclear extracts from HeLa cells, VPA inhibits HDACs with IC50 values from 0.5mM to 2mM [1, 2].
参考文献:
[1] Phiel C J, Zhang F, Huang E Y, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. Journal of Biological Chemistry, 2001, 276(39): 36734-36741.
[2] Chateauvieux S, Morceau F, Dicato M, et al. Molecular and therapeutic potential and toxicity of valproic acid. BioMed Research International, 2010, 2010.
| Kinase experiment [1]: | |
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In vitro Kinase assays |
For in vitro HDAC assays, myc epitope-tagged HDAC1 was transfected into HeLa cells and immunoprecipitated. Immunoprecipitates were washed, resuspended in HD buffer (20 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10% glycerol), and stored as frozen aliquots. HDAC1 was then added to a tube containing 40,000 cpm 3H-labeled acetylated histones (purified from HeLa cells) in 200 μl of HD buffer ±valproic acid,. After rotation for 2 h at 37 °C, the reaction was stopped by the addition of 50 μl of stop solution and released 3H-labeled acetic acid was extracted and analyzed by scintillation counting. |
| Cell experiment [1, 2]: | |
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Cell lines |
Neuro2A cells, human ovarian cancer cell line SKOV3 |
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Preparation method |
Soluble in DMSO. 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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Reacting condition |
0.5–5 mM for 24 h; or 4 mM for 48 h |
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Applications |
Valproic acid induced hyperacetylation of endogenous histones and inhibited nuclear HDAC activity in Neuro2A cells. Moreover, valproic acid inhibited cell proliferation, and induced apoptosis of SKOV3 cells in a dose- and time- dependent manner. |
| Animal experiment [2, 3]: | |
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Animal models |
human ovarian cancer model transplanted subcutaneously in nude mice |
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Dosage form |
500mg/kg/day, intraperitoneal injection, for 30 days |
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Applications |
Valproic acid induced growth inhibition of human ovarian cancer transplanted subcutaneously in nude mice. Moreover, valproic acid (50 mg/kg, IV infusion) decreased pro-inflammatory cytokine gene expression in a canine endotoxemia model in vivo. |
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Other notes |
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. Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A. and Klein, P. S. (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 276, 36734-36741 2. Shan, Z., Feng-Nian, R., Jie, G. and Ting, Z. (2012) Effects of valproic acid on proliferation, apoptosis, angiogenesis and metastasis of ovarian cancer in vitro and in vivo. Asian Pac J Cancer Prev. 13, 3977-3982 3. Song, R., Yu, D., Yoon, J. and Park, J. (2015) Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo). Vet Immunol Immunopathol. 166, 132-137 |
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