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Berlin Brandenburg

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  • 1
    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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  • 2
    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
    Library Location Call Number Volume/Issue/Year Availability
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