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Valproic acid inhibits human hepatocellular cancer cells growth in vitro and in vivo
Marcel Cerqueira Cesar Machado, Marta Bellodi-Privato, Márcia Saldanha Kubrusly, Nilza Aparecida Trindade Molan, Tharcisio Tortelli Junior, Erika Rodrigues de Oliveira and Luiz Augusto Carneiro D’Albuquerque

Background: 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.

Methods: 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 16mg 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.

Results: 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.

Conclusion: VPA inhibits the growth of HCC in vitro and in vivo, suggesting that it could be used in the treatment of HCC alone or in combination with other drugs.

Keywords: valproic acid, hepatocellular carcinoma, apoptosis, Notch-1 gene

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