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  • Ogbomo, Henry  (8)
  • ScienceDirect Journals (Elsevier)  (8)
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  • 1
    Language: English
    In: Trends in Molecular Medicine, 2011, Vol.17(8), pp.433-441
    Description: Malignant gliomas (MGs) are deadly brain tumors with a median survival after resection, radiotherapy and chemotherapy of only 12 months. The natural immunosuppressive state of MG patients and the locally restricted growth of MGs render this neoplasm an excellent target for immunotherapy. Consequently, several failed attempts were made to treat MGs with immune cells. Recent preclinical experimental studies, however, demonstrate that natural killer (NK) cells can kill MGs and therefore hold promise in immunotherapy of MGs. This review describes the experimental and clinical evidence that support the potential of NK cells in therapy of MGs as well as the limitations to NK therapy. Finally, we propose strategies that could circumvent mitigating factors and enhance NK cell therapy for MG patients.
    Keywords: Medicine ; Biology
    ISSN: 1471-4914
    E-ISSN: 1471-499X
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  • 2
    Language: English
    In: Biochemical Pharmacology, 2011, Vol.81(2), pp.251-258
    Description: Enzastaurin is a selective protein kinase Cβ inhibitor which is shown to have direct antitumor effect as well as suppress glycogen synthase kinase-3β (GSK-3β) phosphorylation (resulting in its activation) in both tumor tissues and peripheral blood mononuclear cells (PBMC). It is currently used in phase II trials for the treatment of colon cancer, refractory glioblastoma and diffuse large B cell lymphoma. In this study, the direct effect of enzastaurin on effector function of human natural killer (NK) cells was investigated. The results obtained showed that enzastaurin suppressed both natural and antibody-dependent cellular cytotoxicity (ADCC) of NK cells against different tumor targets. This inhibition was associated with a specific down-regulation of surface expression of NK cell activating receptor NKG2D and CD16 involved in natural cytotoxicity and ADCC respectively, as well as the inhibition of perforin release. Analysis of signal transduction revealed that enzastaurin activated GSK-3β by inhibition of GSK-3β phosphorylation. Treatment of NK cells with GSK-3β-specific inhibitor TDZD-8 prevented enzastaurin-induced inhibition of NK cell cytotoxicity. Apart from the known antitumor and antiangiogenic effects, these results demonstrate that enzastaurin suppresses NK cell activity and may therefore interfere with NK cell-mediated tumor control in enzastaurin-treated cancer patients.
    Keywords: Antibody-Dependent Cellular Cytotoxicity ; Natural Cytotoxicity ; Nkg2d ; Protein Kinase Cβ ; Glycogen Synthase Kinase-3β ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 3
    Language: English
    In: Biochemical Pharmacology, 15 January 2010, Vol.79(2), pp.188-197
    Description: Ribavirin, a broad-spectrum anti-viral drug, exhibits immunomodulatory activities. To study direct effects of ribavirin on natural killer (NK) cell effector functions and signaling, resting NK cells and interleukin (IL)-15-activated NK cells were treated for 5 days with therapeutic ribavirin concentrations ranging from 5 μg/ml to 20 μg/ml. Both resting and IL-15-activated NK cells that were not treated with ribavirin were used as control. Cytotoxicity assays, flow cytometry, enzyme linked immunosorbent assays, and Western blot experiments were performed to elucidate ribavirin effect on NK cells. Results showed that ribavirin (not toxic at concentrations tested; IC 〉 80 μg/ml) had no influence on lysis of target cells by freshly isolated NK cells. Conversely, ribavirin dose-dependently inhibited lysis of target cells by up to 66% and impaired interferon gamma production when IL-15-activated NK cells were used. IL-15-induced increased expression and hence function of NK cell activating receptors including NKp30, NKp44, NKp46 and NKG2D were selectively down-regulated and impaired. These inhibitory effects were associated with the down-regulation of IL-15 receptor beta and gamma expression. Accordingly, downstream events involved in NK cell signaling via IL-15 receptors including the activation of Janus kinase (Jak)-1, signal transducer and activator of transcription STAT-1, STAT-3, and STAT-5 as well as pathways responsible for NK cell degranulation including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were impaired. These results reveal a novel mechanism by which ribavirin exerts its immunomodulatory activities.
    Keywords: Nk Cell Activating Receptors ; Nk Cell Signaling ; Nk Cell Degranulation ; Perforin and Granzyme B Release ; Il-15 Receptors ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 4
    Language: English
    In: Biochemical and Biophysical Research Communications, 2006, Vol.339(1), pp.375-379
    Description: The measurement of natural killer (NK) cells toxicity against tumor or virus-infected cells especially in cases with small blood samples requires highly sensitive methods. Here, a coupled luminescent method (CLM) based on glyceraldehyde-3-phosphate dehydrogenase release from injured target cells was used to evaluate the cytotoxicity of interleukin-2 activated NK cells against neuroblastoma cell lines. In contrast to most other methods, CLM does not require the pretreatment of target cells with labeling substances which could be toxic or radioactive. The effective killing of tumor cells was achieved by low effector/target ratios ranging from 0.5:1 to 4:1. CLM provides highly sensitive, safe, and fast procedure for measurement of NK cell activity with small blood samples such as those obtained from pediatric patients.
    Keywords: Nk Cells ; Cytotoxicity ; Polio Virus Receptor ; Coupled Luminescent Method ; Neuroblastoma Cells ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 5
    Language: English
    In: FEBS Letters, 03 April 2007, Vol.581(7), pp.1317-1322
    Description: Treatment of transformed cells from leukemia or solid tumors with histone deacetylase inhibitors (HDACi) was shown to increase their sensitivity to NK cell lysis. In this study, treatment of IL-2-activated NK cells with HDACi including suberoylanilide hydroxamic acid and valproic acid was studied. Both drugs at therapeutic concentrations inhibited NK cell cytotoxicity on human leukemic cells. This inhibition was associated with decreased expression and function of NK cell activating receptors NKp46 and NKp30 as well as impaired granule exocytosis. NFκB activation in IL-2-activated NK cells was inhibited by both HDACi. Pharmacologic inhibition of NFκB activity resulted in similar effects on NK cell activity like those observed for HDACi. These results demonstrate for the first time that HDACi prevent NK cytotoxicity by downregulation of NK cell activating receptors probably through the inhibition of NFκB activation.
    Keywords: Cytotoxicity ; Nk Cells ; Histone Deacetylase Inhibitors ; Nk Cell Activating and Inhibitory Receptors ; Nuclear Factor Kappa B ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 6
    Language: English
    In: Neoplasia, December 2008, Vol.10(12), pp.1402-1410
    Description: Prolonged treatment of leukemic cells with chemotherapeutic agents frequently results in development of drug resistance. Moreover, selection of drug-resistant cell populations may be associated with changes in malignant properties such as proliferation rate, invasiveness, and immunogenicity. In the present study, the sensitivity of cytarabine (1-β- -arabinofuranosylcytosine, araC)-resistant and parental human leukemic cell lines (T-lymphoid H9 and acute T-lymphoblastic leukemia Molt-4) to natural killer (NK) cell-mediated killing was investigated. The results obtained demonstrate that araC-resistant H9 and Molt-4 (H9 ARAC and Molt-4 ARAC ) cell lines are more sensitive to NK cell-mediated lysis than their respective parental cell lines. This increased sensitivity was associated with a higher surface expression of ligands for the NK cell-activating receptor NKG2D, notably UL16 binding protein-2 (ULBP-2) and ULBP-3 in H9 ARAC and Molt-4 ARAC cell lines. Blocking ULBP-2 and ULBP-3 or NKG2D with monoclonal antibody completely abrogated NK cell lysis. Constitutive phosphorylated extracellular signal-regulated kinase (ERK) but not pAKT was higher in araC-resistant cells than in parental cell lines. Inhibition of ERK using ERK inhibitor PD98059 decreased both ULBP-2/ULBP-3 expression and NK cell cytotoxicity. Furthermore, overexpression of constitutively active ERK in H9 parental cells resulted in increased ULBP-2/ULBP-3 expression and enhanced NK cell lysis. These results demonstrate that increased sensitivity of araC-resistant leukemic cells to NK cell lysis is caused by higher NKG2D ligand expression, resulting from more active ERK signaling pathway.
    Keywords: Medicine
    ISSN: 1476-5586
    E-ISSN: 1476-5586
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  • 7
    Language: English
    In: Journal of Clinical Virology, 2009, Vol.46(1), pp.55-60
    Description: For the medical management, it would be of great relevance to get a diagnostic marker predicting the outcome of infection. For this purpose, the envelope antigens of the individual HCV strain in a patient was tested for their capacity to induce neutralizing antibodies and cytotoxic T lymphocytes. A system for the measurement of neutralizing antibodies as well as for the stimulation of a HCV-specific T-cell response using pseudo-typed HCV particles (HCVpp) was established. A report on results of a pilot study conducted with blood specimens of 19 chronically infected patients is also presented. Neutralization of HCVpp could be measured in nearly all HCV sero-positive patient samples. Nevertheless, in more than half of the patient samples (11/19), no HCV-specific CD4+ response was detectable. In addition, HCV-specific CD8+ response was measurable in most of the patients when HCVpp were used for T-cell stimulation. Although the same antigens (HCVpp) were used, there was no relevant correlation between neutralization titers and T-cell response. Our study shows that HCVpp are appropriate antigens for specific stimulation of lymphocytes as well as for the investigation of antibody neutralization activity.
    Keywords: Humoral Immunity ; Cellular Immunity ; T-Cell Simulation ; Neutralization ; Biology
    ISSN: 1386-6532
    E-ISSN: 1873-5967
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  • 8
    Language: English
    In: International Immunopharmacology, 2005, Vol.5(4), pp.757-769
    Description: Polysialic acid (PSA) is a dynamically regulated carbohydrate modification of the neural cell adhesion molecule NCAM, which has been linked to cancer development and dissemination. Two enzymes, the polysialyltransferases ST8SiaIV and ST8SiaII, are known to be involved in the polysialylation of NCAM. The antiepileptic drug valproic acid (VPA) is associated with anti-cancer activity. In this study, VPA blocked the adhesion of several neuroectodermal tumor cell lines to human umbilical vein endothelial cells. Furthermore, VPA induced intracellular PSA accumulation and enhanced expression of PSA-NCAM on the cell surface. Using a semiquantitative RT-PCR strategy, VPA was shown to up-regulate ST8SiaIV mRNA, whereas ST8SiaII mRNA was down-regulated by this compound. Our data indicate that increased expression of ST8SiaIV enables accelerated polysialylation of NCAM, which might be coupled to a loss of adhesive functions of tumor cells.
    Keywords: Valproic Acid ; PSA-Ncam ; St8siaiv ; St8siaii ; Tumor Dissemination ; Biology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1567-5769
    E-ISSN: 1878-1705
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