Valproic acid sodium salt (Sodium valproate)

Valproic acid sodium salt (Sodium valproate) (VPA) is an orally active histone deacetylase (HDAC) inhibitor with an IC₅₀ value of 1.5 mM. It inhibits HDAC1 with an IC₅₀ value of 400 μM and can induce the degradation of HDAC2 ^{[1, 2]}. Valproic acid sodium salt can be used in the study of epilepsy, bipolar disorder, metabolic diseases, HIV infection and migraine ^[3].

In vitro, treatment of HepG2 cells with valproic acid sodium salt (0.5, 1.0, 2.0 mM) for 24-72 h inhibited mitochondrial respiration and caused mitochondrial dysfunction, manifested as decreased matrix metalloproteinases (MMPs), ATP depletion, increased cell death and decreased cell number ^[4]. Treatment of glioma cells (U87MG, SF295 and T98G) with valproic acid sodium salt (1.0 mM) for 96 h increased cellular autophagic vacuoles and induced mitochondrial ROS accumulation ^[5]. Treatment of DMS53 small cell lung cancer cells with valproic acid sodium salt (0-10 mM) for 48 h dose-dependently inhibited cell proliferation, induced the expression of full-length and active forms of Notch1 protein, and suppressed the levels of neuroendocrine tumor markers chromogranin A and ASLC-1^[6].

In vivo, valproic acid sodium salt (500 mg/kg) was intraperitoneally injected into mice transplanted with Kasumi-1 cells, inhibited tumor growth and angiogenesis, suppressed the mRNA and protein expression of VEGF, VEGFR2 and bFGF, downregulated HDAC, and increased histone H3 acetylation and its accumulation on the VEGF promoter^[7].

References:
[1] Eyal S, Yagen B, Shimshoni J, et al. Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active VPA constitutional isomers and derivatives[J]. Biochemical pharmacology, 2005, 69(10): 1501-1508.
[2] 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[J]. Journal of Biological Chemistry, 2001, 276(39): 36734-36741.
[3] Shnayder N A, Grechkina V V, Khasanova A K, et al. Therapeutic and toxic effects of valproic acid metabolites[J]. Metabolites, 2023, 13(1): 134.
[4] Komulainen T, Lodge T, Hinttala R, et al. Sodium valproate induces mitochondrial respiration dysfunction in HepG2 in vitro cell model[J]. Toxicology, 2015, 331: 47-56.
[5] Fu J, Shao C J, Chen F R, et al. Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines[J]. Neuro-oncology, 2010, 12(4): 328-340.
[6] Platta C S, Greenblatt D Y, Kunnimalaiyaan M, et al. Valproic acid induces Notch1 signaling in small cell lung cancer cells[J]. Journal of Surgical Research, 2008, 148(1): 31-37.
[7] Zhang Z H, Hao C L, Liu P, et al. Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi1 leukemia cells[J]. Molecular medicine reports, 2014, 9(2): 443-449.

Valproic acid sodium salt (Sodium valproate)（VPA）是一种具有口服活性的组蛋白脱乙酰酶 （HDAC）抑制剂，IC₅₀ 值为1.5mM，抑制HDAC1的IC₅₀值为400μM，同时可诱导HDAC2的降解^{[1, 2]}。Valproic acid sodium salt可用于癫痫、双相情感障碍、代谢疾病、HIV感染和偏头痛等的研究^[3]。

在体外，Valproic acid sodium salt（0.5、1.0、2.0 mM）处理HepG2细胞24-72h，抑制了线粒体呼吸并导致线粒体功能障碍，表现为基质金属蛋白酶（MMP）减少、ATP耗尽、细胞死亡增加和细胞数量减少^[4]。Valproic acid sodium salt（1.0mM）处理神经胶质瘤细胞（U87MG、SF295和T98G）96h，增加了细胞自噬泡，诱导了线粒体ROS积累^[5]。Valproic acid sodium salt（0-10 mM）处理小细胞肺癌DMS53 细胞48h，剂量依赖性地抑制了细胞增殖，诱导了Notch1蛋白全长和活性形式的表达，抑制了神经内分泌肿瘤标志物嗜铬粒蛋白A和ASLC-1的水平^[6]。

在体内，Valproic acid sodium salt（500mg/kg）通过腹腔注射治疗移植了Kasumi-1细胞的小鼠，抑制了肿瘤生长和血管生成，抑制了VEGF、VEGFR2和bFGF的mRNA和蛋白质表达，下调了HDAC，增加了组蛋白H3乙酰化及其在VEGF启动子上的积累^[7]。