Glioma (high-grade gliomas) is the most common and lethal tumor of the central nervous system, and their treatment involves surgical resection, radiotherapy, and chemotherapy, but these therapeutic strategies have shown limited success in increasing patient survival, which is less than 2 years [1]. Therefore, it is extremely important to develop more effective and specific treatments for this cancer type. Several lines of evidence suggest that the presence of microglia/macrophages in the glioma microenvironment is an essential component of proliferation, migration, and cell survival processes [2–4]. In recent years, many studies have been conducted to better understand the mechanisms involved in glioma progression. In this context, the P2X7 receptor (P2X7R) has attracted great interest.
In the present work, “P2X7 receptor antagonism inhibits tumors growth in human high-grade gliomas”, the authors put forward a hypothesis largely based on previous studies from their laboratory: (i) glioma tumor cells and tumor-associated microglia from human gliomas express P2X7R, and the latter presents functional P2X7R with pore opening ability [5]; (ii) P2X7R pore activation causes IL-1β release, which in turn drives microglia activation and proliferation [6]. This is in keeping with previous reports showing that the P2X7R promotes glioma growth and progression [7–11], though other studies show that P2X7R inhibition increases in vitro and in vivo glioma growth [12, 13]. A possible explanation for these contrasting results could be the heterogeneity of glioma models used (cell lines isolated from mouse, rat, and human), since each cell line has its own characteristics and different levels of P2X7R expression [14]. Therefore, the role of P2X7R in glioma growth remains unclear.
The paper by Kan and collaborators sheds new light on the role played by the P2X7R in high-grade glioma growth. In this study, the effect of P2X7R antagonists (brilliant blue G (BBG), oxidized ATP (oATP), and AZ10606120) on the U251 glioma cell line and in human primary cells from patients with high-grade glioma was investigated. The use of human primary glioma cells is of great experimental value because this cell model might retain in vitro some of the properties dictated by glioma microenvironment, providing crucial information on the regulation of P2X7R responses in the tumor core. Moreover, the authors compared the effect of AZ10606120 with temozolomide (chemotherapy agent used to treat glioma patients, but this molecule only increases the survival by few months).
The authors confirmed the presence of the P2X7R in glioma and its sensitivity to AZ10606120, BBG, or oATP-mediated inhibition. However, only AZ10606120 decreased proliferation of U251 and glioma cell samples. These results are intriguing and will deserve close attention in future studies. It might be that AZ10606120 was a more effective antagonist due to its higher affinity, potency, and selectivity compared with BBG or oATP. A most interesting result in this study was the demonstration that AZ10606120 was more potent than temozolomide in decreasing the proliferation of the U251 glioma cell line. Since temozolomide is the gold standard for glioma chemotherapy, these data highlight the potential of P2X7R as a new therapeutic target. This study opens an encouraging therapeutic perspective, but at the same time raises several questions, as hinted by the authors themselves: (i) a thorough investigation of the effects of AZ10606120 on P2X7R functions in human glioma cells is needed; (ii) the effect of the combined administration of AZ10606120 and temozolomide should be explored; (iii) the effect of AZ10606120 on microglia should be characterized. In conclusion, the study by Kan and co-workers provides sound data to support P2X7R targeting in the therapy of glioma.
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Conflict of interest
Leticia Scussel Bergamin declares that he/she has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
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