Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

Abstract

Objective: 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. Methods: 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. Results: 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 D 0.047). Conclusions: The VPA-induced increase in NKG2D ligands expression significantly enhanced the effects of CIK cell therapy in a mouse model of HCC.

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

“…In human hepatocytes, the ERK pathway can be activated by VPA exposure . Given that both melatonin and VPA have been reported to prevent tumor growth and progression in animal models of cancer , it would be interesting to determine the combinatorial effects in vivo in our future studies.…”

Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up

“…Second, CIK cells could be stimulated by upregulating the expression of major histocompatibility complex (MHC) class I-related chain (MIC)-A and -B, which bind to natural killer group 2 member D (NKG2D) and activate CIK cells. Our group recently reported that histone deacetylase inhibitors such as suberoylanilide hydroxamic acid and valproate enhance the expression of MIC-A and -B in an epigenetic manner [ 45 ]; therefore, combination therapy with these agents could also be considered. Third, combination treatment with different types of adoptive immunotherapy such as dendritic cell vaccine could be utilized.…”

Cytokine-induced killer cells as a feasible adoptive immunotherapy for the treatment of lung cancer

“…Few clinical studies have confirmed the role of CIKs in the maintenance therapy of advanced lung cancer patients. CIKs, alone or in combination with other therapies, have proven safe and efficient in clinical practice 22 – 24 , 29 , 30 . CIK cells consist of a heterogeneous cell population, with the primary population comprising CD3 + CD56 − and CD3 + CD56 + cells and a minor population of CD3 − CD5 + cells 13 .…”