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Influence of NSAIDs and methotrexate on CD73 expression and glioma cell growth
Daniela Vasconcelos Lopes1, Amanda de Fraga Dias2, Luiz Fernando Lopes Silva2
1Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Abstract:
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.
Insights
Methotrexate (MTX) increases CD73 expression in glioblastoma (GBM) cells, reducing cell viability. This effect occurs independently of the adenosinergic system, suggesting novel therapeutic avenues for this deadly brain tumor.
Area of Science:
- Neuro-oncology
- Immunology
- Pharmacology
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor.
- CD73 enzyme overexpression in GBM regulates extracellular adenosine, an immunosuppressive molecule.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) show potential antiproliferative effects.
Purpose of the Study:
- To investigate the impact of various NSAIDs and MTX on CD73 expression in GBM and mononuclear cells.
- To determine if MTX's effects are mediated by CD73 expression and activity.
- To elucidate the mechanism of MTX's action in the GBM microenvironment.
Main Methods:
- Assessed cell viability and CD73 expression in GBM (C6) and mononuclear cells upon NSAID exposure.
- Investigated MTX's mechanism using CD73 inhibitors (APCP), adenosine uptake inhibitors (dipyridamole), adenosine kinase inhibitors (ABT-702), and adenosine receptor antagonists (caffeine).
Main Results:
- Only MTX significantly increased CD73 expression in GBM cells.
- MTX decreased GBM cell viability through mechanisms independent of the adenosinergic system.
- NSAIDs did not show significant modulation of CD73 expression in this context.
Conclusions:
- MTX exhibits anti-GBM activity by upregulating CD73, independent of adenosine signaling.
- Further research is required to fully understand MTX's role and potential in GBM treatment.
- The adenosinergic system is not the primary mediator of MTX's antiproliferative effects in GBM.
