Tumor growth inhibitory activity of the P2X7 receptor antagonist AZ10606120 in two cell lines of human glioblastoma

TL;DR

This study shows that blocking the P2X7 receptor with AZ10606120 reduces the growth of human glioblastoma cells, but also activates pathways that could promote tumor progression.

Contribution

The study reveals the dual effect of AZ10606120 on glioblastoma cells, inhibiting growth while activating pro-tumor signaling.

Findings

AZ10606120 significantly reduced GBM cell viability and proliferation.

AZ10606120 increased caspase-3 and p21 expression, suggesting apoptosis induction.

AZ10606120 stimulated IL-6 release and activated CREB and STAT3 pathways.

Abstract

Glioblastoma multiforme (GBM) is among the most aggressive and lethal primary brain tumors. P2X7 is a purinergic receptor overexpressed in GBM, whose activation can promote tumor growth. Two major splice variants of the P2X7 receptor, isoforms A and B, are expressed in GBM cells. In our study, both isoforms A and B were present in GBM cells, with a slight prevalence of isoform B expression in the U87MG cell line compared to the T98G cell line. In GBM cell cultures, we evaluated the effects of P2X7 receptor activation/inhibition on cell growth. Exposure of GBM cells to various concentrations of ATP did not alter cellular activity, whereas inhibition of the P2X7 receptor with the antagonist AZ10606120, but not with A740003, significantly reduced GBM cell viability and proliferation. The U87MG cell line, which expresses the B isoform more highly, was more sensitive to the antiproliferative effects of AZ10606120. To clarify the mechanisms of AZ10606120-induced tumor inhibition, we measured the expression of proteins involved in cell repair and survival processes. AZ10606120 induced an increase in caspase-3 and p21 expression, demonstrating that P2X7R blockade can induce tumor cell death, likely by apoptosis. AZ10606120 also stimulated interleukin-6 (IL-6) release in GBM cells and induced phosphorylation of CREB and STAT3. Blockade of P2X7R by AZ10606120 appears to activate a pro-tumor IL-6/STAT3 axis. Increased IL-6 secretion and activation of the CREB and STAT3 pathways are negative prognostic signs that highlight the need to combine P2X7R inhibition with AZ10606120 with other therapies.

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