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The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3?.

Ogbomo, Henry, Biru, Tsigereda, Michaelis, Martin, Loeschmann, Nadine, Doerr, Hans Wilhelm, Cinatl, Jindrich (2011) The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3?. Biochemical Pharmacology, 81 (2). pp. 251-8. ISSN 0006-2952. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)

Abstract

Enzastaurin is a selective protein kinase C? inhibitor which is shown to have direct antitumor effect as well as suppress glycogen synthase kinase-3? (GSK-3?) 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-3? by inhibition of GSK-3? phosphorylation. Treatment of NK cells with GSK-3?-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.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 05 Jun 2013 17:32 UTC
Last Modified: 29 May 2019 10:14 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34064 (The current URI for this page, for reference purposes)
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