Machado Marcel Cerqueira Cesar, Bellodi-Privato Marta, Kubrusly Márcia Saldanha, Molan Nilza Aparecida Trindade, Tharcisio Tortelli, de Oliveira Erika Rodrigues, D'Albuquerque Luiz Augusto Carneiro
São Paulo University, School of Medicine, Department of Gastroenterology (LIM-37), Brazil.
J Exp Ther Oncol. 2011;9(2):85-92.
Valproic acid (VPA) a histone deacetylase inhibitor has been shown to inhibit the growth of a variety of cancer cells. We examined the effect of VPA in human hepatocellular cancer cells (HuH7) in vitro and in vivo. We hypothesized that VPA may be able to modulate Notch-1 signaling in hepatic carcinoma cells, with antitumor effects.
HuH7 cells were used in this study. The inhibition of cell proliferation was determined by MTT assay. A caspase assay was used to determine the enzymatic activity of caspase-3. The impact of the activation or inhibition on HuH7 cell cycling was examined by FACS. analysis. HuH7 cells were injected subcutaneously in athymic male BALB/c mice. Animals were divided into two groups of 14 animals each (Group I non-treated and Group II treated). Group II received 16 mg daily of VPA orally for 30 days. Tumor size and volumes were measured and calculated until the end of the experiment. Notch-1 mRNA levels in HuH7 cells and tumor samples were assessed by qRT-PCR.
VPA suppressed tumor cell proliferation in a dose-dependent manner. A significant statistical difference regarding DNA degradation and an increased activity of caspase-3 were observed in treated cells in comparison to non-treated cells. We observed a significant reduction of tumor xenografted growth and a significant down-regulation of Notch-1 mRNA levels in Group II.
VPA inhibits the growth of HOC in vitro and in vivo, suggesting that it could be used in the treatment of HCC alone or in combination with other drugs.
丙戊酸（VPA）作为一种组蛋白去乙酰化酶抑制剂，已被证明可抑制多种癌细胞的生长。我们在体外和体内研究了VPA对人肝癌细胞（HuH7）的作用。我们推测VPA可能能够调节肝癌细胞中的Notch-1信号通路，从而发挥抗肿瘤作用。
本研究使用HuH7细胞。通过MTT法测定细胞增殖抑制情况。使用半胱天冬酶检测法测定半胱天冬酶-3的酶活性。通过流式细胞术分析检测激活或抑制对HuH7细胞周期的影响。将HuH7细胞皮下注射到无胸腺雄性BALB/c小鼠体内。动物分为两组，每组14只（I组为未治疗组，II组为治疗组）。II组每天口服16 mg VPA，持续30天。在实验结束前测量并计算肿瘤大小和体积。通过qRT-PCR评估HuH7细胞和肿瘤样本中Notch-1 mRNA水平。
VPA以剂量依赖性方式抑制肿瘤细胞增殖。与未处理细胞相比，处理后的细胞在DNA降解和半胱天冬酶-3活性增加方面存在显著统计学差异。我们观察到II组肿瘤异种移植生长显著减少，Notch-1 mRNA水平显著下调。
VPA在体外和体内均抑制肝癌细胞生长，表明它可单独或与其他药物联合用于肝癌治疗。
