title: Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model.
abstract: Long-term prognosis of hepatocellular carcinoma (HCC) remains poor owing to the lack of treatment options for advanced HCC. Cytokine-induced killer (CIK) cells are ex vivo expanded T lymphocytes expressing both NK- and T-cell markers. CIK cell therapy alone is insufficient for treating advanced HCC. Thus, this study aimed to determine whether treatment with CIK cells combined with valproic acid (VPA) could provide a synergistic effect to inhibit tumor growth in a mouse model of HCC.
  
  
  
  Upregulation of natural killer group 2D (NKG2D) ligands (retinoic acid early inducible 1 [RAE-1], mouse; major histocompatibility complex class I polypeptide-related sequence A [MIC-A], human) were evaluated by FACS. VPA concentrations that did not reduce tumor volume were calculated to avoid VPA cytotoxicity in a C3H mouse model of HCC. CIK cells were generated from mouse splenocytes using interferon gamma, a CD3 monoclonal antibody, and interleukin 2. The potential synergistic effect of CIK cells combined with VPA was evaluated in the mouse model and tissue pathology was investigated.
  
  
  
  After 40 h of incubation with VPA, RAE-1 and MIC-A expression were increased in 4 HCC cell lines compared with that in control (2.3-fold in MH-134, 2.4-fold in Huh-7, 3.7-fold in SNU-761, and 6.5-fold in SNU-475). The maximal in vivo VPA dosage that showed no significant cytotoxicity compared with control was 10 mg/kg/day. CIK cells were well generated from C3H mouse splenocytes. After 7 d of treatment with CIK cells plus VPA, a synergistic effect was observed on relative tumor volume in the mouse model of HCC. While the relative tumor volume in untreated control mice increased to 11.25, that in the combination treatment group increased to only 5.20 (P = 0.047).
  
  
  
  The VPA-induced increase in NKG2D ligands expression significantly enhanced the effects of CIK cell therapy in a mouse model of HCC.
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.|b Department of Internal Medicine , Seoul Metropolitan Government-Seoul National University Boramae Medical Center , Seoul , Korea.
authors.forename: Dong Hyeon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Joon Yeul
authors.initials: JY
authors.lastname: Nam
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Chang
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Hyeki
authors.initials: H
authors.lastname: Cho
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Seong Hee
authors.initials: SH
authors.lastname: Kang
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Young Youn
authors.initials: YY
authors.lastname: Cho
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: EunJu
authors.initials: E
authors.lastname: Cho
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: a Department of Internal Medicine and Liver Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D055612:Cytokine-Induced Killer Cells / Q000276:immunology* / Q000637:transplantation*; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014635:Valproic Acid
keywords: Cancer immunology; hepatocellular carcinoma; immunotherapy