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Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model


, : Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. International Journal of Cancer 132(4): 843-853

Lactate formation in highly proliferative tumours such as malignant gliomas is associated with poor survival and contributes to the suppression of local immunity. Here we report, that diclofenac used at non-toxic concentrations significantly decreased lactate production in murine glioma cells and inhibited the expression of lactate dehydrogenase-A (LDH-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-1 secretion upon Toll-like receptor stimulation with R848 that correlated with reduced lactate levels in the glioma cell co-culture and a blockade of signal transducers and activators of transcription 3 (Stat3) phosphorylation. In vivo, diclofenac treatment diminished intratumoural lactate levels and resulted in a significant delay of glioma growth. Ex vivo analyses revealed that tumour-infiltrating DCs regained their capacity to produce IL-12 upon R848-stimulation. Moreover, diclofenac reduced the number of tumour-infiltrating regulatory T cells (Tregs) and impaired the upregulation of the Treg activation marker CD25. Nevertheless, a single intratumoural 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-? production and T cell proliferation indicating that immunotherapeutic approaches have to be carefully timed when combined with diclofenac. In summary, diclofenac appears an attractive agent for targeting lactate production and counteracting local immune suppression in malignant gliomas.

US$19.90

PMID: 22752934

DOI: 10.1002/ijc.27712


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