| Dokumentenart: | Artikel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Titel eines Journals oder einer Zeitschrift: | International Journal of Cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Verlag: | Wiley | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Band: | 132 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Seitenbereich: | S. 843-853 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Datum: | 15 Februar 2013 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Institutionen: | Medizin > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medizin > Zentren des Universitätsklinikums Regensburg > Zentrum für Hirntumore (ZHT) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Stichwörter / Keywords: | diclofenac; lactate; LDH-A; Stat3; dendritic cell; TLR; regulatory T cell; glioma | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dewey-Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik > 500 Naturwissenschaften 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Veröffentlicht | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| An der Universität Regensburg entstanden: | Ja | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dokumenten-ID: | 30515 |
Zusammenfassung
Lactate formation in highly proliferative tumors such as malignant gliomas is associated with poor survival and contributes to the suppression of local immunity. Here, we report that diclofenac used at nontoxic concentrations significantly decreased lactate production in murine glioma cells and inhibited the expression of lactate dehydrogenase-A in vitro. Lactate reduction was accompanied by a ...
Zusammenfassung
Lactate formation in highly proliferative tumors such as malignant gliomas is associated with poor survival and contributes to the suppression of local immunity. Here, we report that diclofenac used at nontoxic concentrations significantly decreased lactate production in murine glioma cells and inhibited the expression of lactate dehydrogenase-A in vitro. Lactate reduction was accompanied by a dose-dependent inhibition of cell growth and a cell cycle arrest at the G2/M checkpoint. In the presence of diclofenac, murine bone marrow-derived dendritic cells (DCs) showed enhanced IL-12, but decreased IL-10 secretion on Toll-like receptor stimulation with R848 that correlated with reduced lactate levels in the glioma cell coculture and a blockade of signal transducers and activators of transcription 3 phosphorylation. In vivo, diclofenac treatment diminished intratumoral lactate levels and resulted in a significant delay of glioma growth. Ex vivo analyses revealed that tumor-infiltrating DCs regained their capacity to produce IL-12 on R848 stimulation. Moreover, diclofenac reduced the number of tumor-infiltrating regulatory T cells and impaired the upregulation of the Treg activation marker CD25. Nevertheless, a single intratumoral injection of R848 combined with diclofenac failed to induce an additional survival advantage in glioma-bearing mice. Further analyses illustrated that the presence of diclofenac during T-cell activation compromised INF-γ production and T-cell proliferation, indicating that immunotherapeutic approaches have to be carefully timed when combined with diclofenac. In summary, diclofenac appears as an attractive agent for targeting lactate production and counteracting local immune suppression in malignant gliomas.
Metadaten zuletzt geändert: 29 Sep 2021 07:40
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