title: Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model.
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-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.
authors: Department of Neurology, University Medical Centre of Regensburg, Regensburg, Germany.
authors: Sridhar R
authors: SR
authors: Chirasani
authors: Petra
authors: P
authors: Leukel
authors: Eva
authors: E
authors: Gottfried
authors: Jochen
authors: J
authors: Hochrein
authors: Katrin
authors: K
authors: Stadler
authors: Bernhard
authors: B
authors: Neumann
authors: Peter J
authors: PJ
authors: Oefner
authors: Wolfram
authors: W
authors: Gronwald
authors: Ulrich
authors: U
authors: Bogdahn
authors: Peter
authors: P
authors: Hau
authors: Marina
authors: M
authors: Kreutz
authors: Oliver M
authors: OM
authors: Grauer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D053645:Interleukin-2 Receptor alpha Subunit; D007527:Isoenzymes; D016753:Interleukin-10; D004008:Diclofenac; D018664:Interleukin-12; D019344:Lactic Acid; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C402365:resiquimod