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ABSTRACT: Hedgehog (Hh) signaling is activated in various types of cancer and contributes to the progression, proliferation, and invasiveness of cancer cells. Many Hh inhibitors are undergoing clinical trial and show promise as anticancer drugs. Hh signaling is also induced in the activated T and NK (TNK) lymphocytes that are used in immunotherapy. Activated TNK lymphocyte therapy is anticipated to work well within a tumor's hypoxic environment. However, most studies on the immunobiological functions of activated TNK lymphocytes have been conducted on healthy donor samples, under normoxic conditions. In the present study, we evaluated the effects of Hh inhibition and oxygen concentrations on the function of activated TNK lymphocytes derived from patients with advanced cancer. Proliferation, migration, surface NKG2D expression, and cytotoxicity were all significantly inhibited, and IFN-γ secretion was significantly increased upon Hh inhibitor treatment of activated TNK lymphocytes under hypoxic conditions in vitro. Tumors from mice injected with cyclopamine-treated activated TNK lymphocytes showed a significant increase in tumor size and had fewer apoptotic cells compared with the tumors in mice injected with control activated TNK lymphocytes. These results suggest that Hh signaling plays a pivotal role in activated TNK lymphocyte cell function. Combination therapy using Hh inhibitors and activated TNK lymphocytes derived from patients with advanced cancer may not be advantageous.
Cancer Immunology and Immunotherapy 04/2013; · 3.70 Impact Factor
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ABSTRACT: Aim: Sorafenib is a promising treatment for hepatocellular carcinoma (HCC) but recent toxicity concerns suggest that new strategies for its use are needed. One approach for reducing toxicity is to use lower doses of sorafenib in combination with other complementary mechanisms. Celecoxib, a cyclooxygenase-2 inhibitor, has been shown to inhibit HCC, and we hypothesized that low-dose sorafenib co-administered with celecoxib could act synergistically in the inhibition of HCC. In this study, the effect of sorafenib was tested in combination with celecoxib on the growth of human HCC cells in vitro.
Two human HCC cell lines, HepG2 and Huh7, were treated with sorafenib and celecoxib, alone and in combination, and the effect of these treatments on growth, apoptosis, and expression of phospho-AKT was evaluated by WST-8, DNA content, and immunocytochemical assays, respectively.
When compared to the actions of either agent alone, the combination of low concentrations of sorafenib (<5 μM) and celecoxib (<20 μM) resulted in enhanced inhibition of both cell growth and AKT activation, and increased the induction of apoptosis. Combination index (CI) analysis showed that the growth inhibition effect was synergistic.
This study shows that celecoxib synergistically potentiates the sorafenib-mediated antitumor effect. This finding establishes the foundation for clinical trials evaluating the efficacy of co-administration of soerafenib and celecoxib as a treatment for HCC.
Anticancer research 04/2013; 33(4):1387-95. · 1.73 Impact Factor
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ABSTRACT: We explored the possibility of combining adoptive immunotherapy with cytokine-activated killer (CAK) cells and the epidermal growth factor receptor monoclonal antibody, cetuximab, as a treatment for cholangiocarcinoma.
CAK cells were cultured with a high-dose of interleukin-2 and anti-CD3 monoclonal antibodies. This cell population contained both activated CD16+/CD56+ (NK) cells and CD3+/NKG2D(high+) T-cells. The effect of CAK cells and cetuximab, alone and in combination, on the viability of human cholangiocarcinoma cells was evaluated.
Culture of CAK cells alone, but not cetuximab alone, exhibited modest cytotoxicity toward cholangiocarcinoma cells. However, combining CAK cells with cetuximab significantly enhanced cytotoxicity. This enhancement was inhibited by the addition of excess human immunoglobulins, suggesting that antibody-dependent cytotoxicity, mediated by activated NK cells in the CAK cell culture was involved in this mechanism.
Cetuximab may be used to enhance CAK cell therapeutic activity in patients with cholangiocarcinoma, by potentiating antibody-dependent cellular cytotoxicity.
Anticancer research 06/2012; 32(6):2249-56. · 1.73 Impact Factor
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ABSTRACT: Immunotherapy using cytotoxic T-lymphocytes (CTLs) still has limited success. An increase in the frequency of CTL administration is one method to improve immunotherapy using CTLs. The conventional method (C-method) that generates CTLs after the induction of dendritic cells requires a long time period. If CTLs can be more rapidly and simply induced, the frequency of immunotherapy could be increased and unexpected contamination could be avoided. In this study, in order to more rapidly induce functional CTLs, we investigated a new method (N-method) that uses a cytokine cocktail, including interleukin (IL)-2, IL-4, granulocyte macrophage colony-stimulating factor, tumour necrosis factor-α and interferon-α, together with a tumour lysate. CTLs induced by the N-method had equivalent functions, such as proliferation, surface antigen expression and cytotoxicity, compared with those induced by the C-method. These results suggest that the N-method can substitute the C-method in order to improve the effect of immunotherapy using CTLs.
Anticancer research 06/2012; 32(6):2385-90. · 1.73 Impact Factor
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ABSTRACT: Natural-killer group 2, member D (NKG2D) is an activating receptor on natural killer cells and activated T-cells, designated cytokine-activated killer (CAK) cells here. The MHC class I chain-related A and B (MICA and MICB, respectively) are ligands of NKG2D and are expressed on various human tumor cells, including hepatocellular carcinoma (HCC) cells. Here, we investigate whether gemcitabine, a chemotherapeutic agent, affects MICA/B expression in HCC.
We used ELISA, RT-PCR and adherent target detachment assays to determine expression of MICA/B in HepG2 HCC cells and the level of cellular cytotoxicity generated by treatment with gemcitabine and/or CAK cells.
Surface expression of MICA/B was evident after gemcitabine treatment, and MICB-specific mRNA was up-regulated. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB significantly reduced cytotoxicity.
Gemcitabine induced MICA/B expression in HepG2 cells, resulting in synergistic enhancement of the cytotoxic effects of NKG2D-high CAK cells. The combination of gemcitabine and CAK cells may have clinical therapeutic significance for HCC.
Anticancer research 07/2011; 31(7):2505-10. · 1.73 Impact Factor
