title: Valproic acid inhibits human hepatocellular cancer cells growth in vitro and in vivo.
abstract: 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 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: São Paulo University, School of Medicine, Department of Gastroenterology (LIM-37), Brazil.
authors.forename: Marcel Cerqueira Cesar
authors.initials: MC
authors.lastname: Machado
authors.forename: Marta
authors.initials: M
authors.lastname: Bellodi-Privato
authors.forename: Márcia Saldanha
authors.initials: MS
authors.lastname: Kubrusly
authors.forename: Nilza Aparecida Trindade
authors.initials: NA
authors.lastname: Molan
authors.forename: Tortelli
authors.initials: T
authors.lastname: Tharcisio
authors.forename: Erika Rodrigues
authors.initials: ER
authors.lastname: de Oliveira
authors.forename: Luiz Augusto Carneiro
authors.initials: LA
authors.lastname: D'Albuquerque
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D014635:Valproic Acid; D053148:Caspase 3