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
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DOI：
10.1002/ijc.27712
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发表时间：
2013-02-15
影响因子：
6.4
通讯作者：
Grauer, Oliver M.
中科院分区：
文献类型：
--
作者：
Chirasani, Sridhar R.;Leukel, Petra;Grauer, Oliver M.
在高度增殖性肿瘤如恶性神经胶质瘤中乳酸盐的形成与较差的存活率相关，并有助于抑制局部免疫。在这里，我们报告说，双氯芬酸在无毒浓度下使用显着降低小鼠胶质瘤细胞的乳酸产生，并抑制乳酸脱氢酶-A的表达在体外。乳酸减少伴随着剂量依赖性的细胞生长抑制和细胞周期停滞在G2/M检查点。在双氯芬酸存在的情况下，小鼠骨髓来源的树突状细胞（DCs）在R848刺激Toll样受体时显示出IL-12分泌增强，但IL-10分泌减少，这与胶质瘤细胞共培养物中乳酸水平降低以及信号转导和转录激活因子3磷酸化的阻断相关。在体内，双氯芬酸治疗降低了肿瘤内乳酸水平，并导致胶质瘤生长显著延迟。离体分析显示，肿瘤浸润DC在R848刺激下恢复其产生IL-12的能力。此外，双氯芬酸减少了肿瘤浸润性调节性T细胞的数量，并损害了Treg活化标志物CD 25的上调。然而，单次瘤内注射R848联合双氯芬酸未能在荷胶质瘤小鼠中诱导额外的生存优势。进一步的分析表明，T细胞活化期间双氯芬酸的存在损害了INF-γ的产生和T细胞增殖，这表明当与双氯芬酸联合使用时，免疫抑制方法必须仔细定时。总之，双氯芬酸似乎是一种有吸引力的药物，用于靶向乳酸产生和抵消恶性胶质瘤的局部免疫抑制。
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.