Chirasani, Sridhar R. and Leukel, Petra and Gottfried, Eva and Hochrein, Jochen and Stadler, Katrin and Neumann, Bernhard and Oefner, Peter J. and Gronwald, Wolfram and Bogdahn, Ulrich and Hau, Peter and Kreutz, Marina and Grauer, Oliver M. (2013) Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. INTERNATIONAL JOURNAL OF CANCER, 132 (4). pp. 843-853. ISSN 0020-7136,
Full text not available from this repository. (Request a copy)Abstract
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-gamma 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | REGULATORY T-CELLS; GROWTH IN-VIVO; DENDRITIC CELLS; TUMOR-GROWTH; POOR-PROGNOSIS; C-MYC; CYCLOOXYGENASE-2; EXPRESSION; RESPONSES; HYPOXIA; diclofenac; lactate; LDH-A; Stat3; dendritic cell; TLR; regulatory T cell; glioma |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Apr 2020 09:57 |
| Last Modified: | 24 Apr 2020 09:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17144 |
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