Glioblastoma is the most prevalent primary brain tumor with survival rate of about 20.5 months. Hence, investigation on the involved signaling pathways to treat the disease is urgently needed. CD73 and adenosine play key roles in tumor invasion, proliferation, angiogenesis, and chemical resistance of cancer cells. Theophylline are known as adenosine A2a receptor antagonists. Current study investigates the plausible impacts of theophylline in the mice model of glioblastoma. Materials and

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... Initially, induction of glioblastoma tumor was performed within 10 days in male Balb/ C mice. Next, the mice were treated with theophylline for 14 days. Garcia's behavioral test was performed. Moreover, histopathological changes in brain tissue were examined using hematoxylin and eosin staining. The expression of A2a and CD73 proteins was assessed by western blotting. Additionally, the expression of VEGF was indicated by immunohistochemistry. Apoptosis was examined by the TUNEL method. Finally, serum levels of MDA and SOD were investigated using the ELISA method. Results: Garcia's behavioral test indicated a reduction in behavioral and cognitive impairments in theophylline-treated mice. Pathological results demonstrated decreased tumor size and angiogenesis in treatment group. The presence of A2a and CD73 proteins were lower in the treated mice. Moreover, immunohistochemistry investigations showed a decline in VEGF expression in brain tissue and angiogenesis in the theophylline-treated group compared to the control group. Finally, serum levels of MDA and SOD were reduced in theophylline-treated mice. Conclusion: Theophylline seem to ameliorate glioblastoma cancer by improving CD73 or adenosine signaling.