Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Purinergic Signal. 2021 Jun;17(2):273-284. doi: 10.1007/s11302-021-09775-w. Epub 2021 Mar 20.
Glioblastoma (GBM) is the most malignant and deadly brain tumor. GBM cells overexpress the CD73 enzyme, which controls the level of extracellular adenosine, an immunosuppressive molecule. Studies have shown that some nonsteroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) have antiproliferative and modulatory effects on CD73 in vitro and in vivo. However, it remains unclear whether the antiproliferative effects of MTX and NSAIDS in GBM cells are mediated by increases in CD73 expression and adenosine formation. The aim of this study was to evaluate the effect of the NSAIDs, naproxen, piroxicam, meloxicam, ibuprofen, sodium diclofenac, acetylsalicylic acid, nimesulide, and ketoprofen on CD73 expression in GBM and mononuclear cells. In addition, we sought to understand whether the effects of MTX may be mediated by CD73 expression and activity. Cell viability and CD73 expression were evaluated in C6 and mononuclear cells after exposure to NSAIDs. For analysis of the mechanism of action of MTX, GBM cells were treated with APCP (CD73 inhibitor), dipyridamole (inhibitor of adenosine uptake), ABT-702 (adenosine kinase enzyme inhibitor), or caffeine (P1 adenosine receptor antagonist), before treatment with MTX and AMP, in the presence or not of mononuclear cells. In summary, only MTX increased the expression of CD73 in GBM cells decreasing cells viability by mechanisms independent of the adenosinergic system. Further studies are needed to understand the role of MTX in the GBM microenvironment.
胶质母细胞瘤（GBM）是最恶性和致命的脑肿瘤。GBM 细胞过度表达 CD73 酶，该酶控制细胞外腺苷的水平，后者是一种免疫抑制分子。研究表明，一些非甾体抗炎药（NSAIDs）和甲氨蝶呤（MTX）在体外和体内对 CD73 具有抗增殖和调节作用。然而，MTX 和 NSAIDs 在 GBM 细胞中的抗增殖作用是否通过 CD73 表达和腺苷形成的增加来介导仍不清楚。本研究旨在评估 NSAIDs 萘普生、吡罗昔康、美洛昔康、布洛芬、双氯芬酸钠、乙酰水杨酸、尼美舒利和酮洛芬对 GBM 和单核细胞中 CD73 表达的影响。此外，我们试图了解 MTX 的作用是否可能通过 CD73 表达和活性来介导。在暴露于 NSAIDs 后，评估 C6 和单核细胞中的细胞活力和 CD73 表达。为了分析 MTX 的作用机制，在用 MTX 和 AMP 处理 GBM 细胞之前，用 APCP（CD73 抑制剂）、双嘧达莫（腺苷摄取抑制剂）、ABT-702（腺苷激酶酶抑制剂）或咖啡因（P1 腺苷受体拮抗剂）处理 GBM 细胞，存在或不存在单核细胞的情况下。总之，只有 MTX 增加了 GBM 细胞中 CD73 的表达，通过独立于腺苷能系统的机制降低细胞活力。需要进一步研究来了解 MTX 在 GBM 微环境中的作用。
