Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Abstract

Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNAalkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-jB pathway that supports the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNAalkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide

“…Possibly, TMZ reduces the intrinsic epileptogenicity of the tumour through a decrease in glutamate levels released from glioma cells 11. Furthermore, a downregulation of glutamate receptors is associated with a reduction in the risk of seizures as well as with increased survival in glioma patients treated with adjuvant TMZ 38. Changes in the peritumoural microenvironment might also be induced, for example, through an inhibition of the immune response or restoring the neurotransmitter synthesis 39 40…”

Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

“…In contrast, mGluR3 inhibition eliminated this constraint and promoted astroglial differentiation [68, 73, 76, 78]. (6) Accordingly to Arcella et al (2005) [73] and Ciceroni et al (2013) [77], MAPK axis supported mGluR3-induced GBM proliferation, (7) since mGluR3 stimulation increased Erk1/2 phosphorylation and its blockade reduced p-Erk1/2 levels. mGluR3 inhibition plus MEK1/2 blockade showed an additive antiproliferative effect on GBM cells [68].…”

“…In this context, Ciceroni et al (2013) showed mGluR3 inhibition enables cytotoxic action of TMZ in GSC cultures [77]. TMZ (250 μM) did not affect cell viability when applied alone, but became toxic when combined with LY 341495 (100 nM) and LY 2389575 (100 nM), two mGluR3 antagonists.…”

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

“…22,23 Compound 1 has also been used as a tool to establish a potential utility for mGlu 2/3 inhibition in the treatment of glioma. 24–27 …”