P2X7 receptor antagonism inhibits tumour growth in human high-grade gliomas
Liyen Katrina Kan1,2, Sinali Seneviratne3, Kate J Drummond4
1Department of Neuroscience, Central Clinical School, Monash University, Level 6, 99 Commercial Rd, Melbourne, VIC, 3004, Australia.
Abstract:
Gliomas, the most common primary brain cancer, are highly infiltrative and extremely difficult to treat. Despite advancements, current treatment is limited, with patients surviving for a median of 14-15 months post-diagnosis. Previous research has demonstrated the upregulation of a purinergic receptor, P2X7R, in human gliomas. P2X7R is expressed on both glioma cells and microglia within the glioma microenvironment. It is hypothesized that P2X7R contributes to tumour growth and proliferation via immune-mediated mechanisms involving tumour cells and surrounding microglia. We sought to elucidate the role of P2X7R in a human glioblastoma cell line (U251) and on surgically resected human glioma samples. We treated U251 and human glioma cultures for 72 h with P2X7R antagonists, Brilliant Blue G (BBG), oxidized ATP (oATP) and AZ10606120. Cell counting via fluorescence confocal microscopy was conducted to assess tumour proliferation. We observed no significant reductions in tumour cell numbers following P2X7R antagonism with BBG (20 μM) and oATP (250 μM) in both U251 cells and human glioma samples. Interestingly, there was a significant reduction in tumour cell number in both U251 cells (p = 0.0156) and human glioma samples (p = 0.0476) treated with varying concentrations of AZ10606120. When compared with the conventional chemotherapeutic agent, temozolomide, AZ10606120 was also found to more effectively inhibit tumour proliferation in U251 cells (p < 0.0001). Our pilot results demonstrate a potential trophic role of P2X7R where its inhibition by AZ10606120, a potent antagonist, hinders glioma growth directly or through the inactivation of microglia. This sheds new light on P2X7R as a therapeutic target for human gliomas.
Insights
The purinergic receptor P2X7R may drive glioma growth. Inhibiting P2X7R with AZ10606120 significantly reduced glioma cell proliferation, offering a potential new therapeutic target for brain cancer.
Area of Science:
- Neuro-oncology
- Immunology
- Pharmacology
Background:
- Gliomas are aggressive primary brain tumors with poor prognoses.
- The purinergic receptor P2X7R (P2X7R) is upregulated in gliomas and expressed on tumor cells and microglia.
- P2X7R is hypothesized to promote glioma growth through immune-mediated mechanisms.
Purpose of the Study:
- To investigate the role of P2X7R in glioma proliferation.
- To evaluate the efficacy of P2X7R antagonists in inhibiting glioma growth in vitro.
Main Methods:
- Human glioblastoma (U251) cells and glioma cultures were treated with P2X7R antagonists (BBG, oATP, AZ10606120).
- Tumor cell proliferation was assessed using cell counting via fluorescence confocal microscopy.
- Drug efficacy was compared to temozolomide.
Main Results:
- BBG and oATP did not significantly reduce tumor cell numbers.
- AZ10606120 significantly reduced glioma cell proliferation in both U251 cells and human glioma samples.
- AZ10606120 demonstrated superior inhibition of tumor proliferation compared to temozolomide in U251 cells.
Conclusions:
- P2X7R inhibition by AZ10606120 hinders glioma growth, potentially by directly affecting tumor cells or inactivating microglia.
- P2X7R antagonism represents a promising therapeutic strategy for human gliomas.
