Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma

Abstract

Object Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well. Methods In this study 9L gliosarcoma cells were treated with a glutamate transporter upregulating agent, thiamphenicol, an antibiotic approved in Europe, which has been shown previously to increase glutamate transporter expression and has recently been validated in a human Phase I biomarker trial for glutamate transporter upregulation. Cells were monitored in vitro for glutamate transporter levels and cell proliferation. In vivo, rats were injected intracranially with 9L cells and were treated with increasing doses of thiamphenicol. Animals were monitored for survival. In addition, postmortem brain tissue was analyzed for tumor size, glutamate transporter levels, and neuron count. Results Thiamphenicol showed little effects on proliferation of 9L gliosarcoma cells in vitro and did not change glutamate transporter levels in these cells. However, when delivered locally in an experimental glioma model in rats, thiamphenicol dose dependently (10–5000 μM) significantly increased survival up to 7 days and concomitantly decreased tumor size from 46.2 mm2 to 10.2 mm2 when compared with lesions in nontreated controls. Furthermore, immunohistochemical and biochemical analysis of peritumoral tissue confirmed an 84% increase in levels of glutamate transporter protein and a 72% increase in the number of neuronal cells in the tissue adjacent to the tumor. Conclusions These results show that increasing glutamate transporter expression in peritumoral tissue is neuroprotective. It suggests that glutamate transporter upregulation for the treatment of gliomas should be further investigated and potentially be part of a combination therapy with standard chemotherapeutic agents.

The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

“…[ 43 ] Sattler and colleagues have recently demonstrated that thiamphenicol, through its upregulation of EAAT2 in peritumoural tissue, may be similarly beneficial. [ 44 ] PPARγ agonists may constitute an additional agent that activates glutamate transport within tumour cells and peritumourally. These agents could be considered for adjunct treatment in current regimens and in combination therapy for dual mechanistic efficacy in sub therapeutic doses to avoid associated adverse effects.…”

Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma

“…In brain tumors, astrocytes sustain glioma growth and invasion, exacerbating neuroinflammation 12 . In the early stages of glioma, astrocytes protect neurons by controlling the uptake of glutamate released by tumor cells 13 , however, as the tumor grows, astrocytes lose their protective role and, in fact, overexpression of GLT-1 prolongs survival in animal models of malignant glioma 14 .…”

Protein Kinase C (PKC) Isozymes and Cancer

“…These results mean that the use of adenosine triphosphate (ATP) competitive inhibitors to treat glioma will be less efficient [191]. In addition, increased expression of glutamate transporters, also known as excitatory amino-acid transporters, leads to prolonged survival and reduced tumor growth in glioma-bearing animals [192]. Further, PKC is involved in the activation and redistribution of glutamate transporters [183,193,194].…”