Glutamate antagonists limit tumor growth

Rzeski, Wojciech; Ikonomidou, Chrysanthy; Turski, Lechosław

doi:10.1016/s0006-2952(02)01218-2

Cited by 108 publications

(114 citation statements)

References 42 publications

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“…An assessment of the direct action of glutamate on cancer cell growth was first reported in the 1950s, although no change in growth was found [48]. Inhibition of NMDA receptors was subsequently demonstrated to inhibit cell growth in a variety of cancer cell lines in standard media conditions [49][50][51]. Using a similar approach to the current study, Abdul and Hoosein [49] reported a moderate decrease in growth with the uncompetitive NMDA antagonist memantine in two of the cell lines that we have tested.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell lines release glutamate into the extracellular environment

Seidlitz

Sharma

Saikali

et al. 2009

Clin Exp Metastasis

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Bone is one of the most frequent sites for metastasis of breast and prostate cancers. Bone metastases are associated with pathologic changes in bone turnover and severe pain. The mechanisms that trigger these effects are not well understood, but it is postulated that tumour cells release factors which interfere with signalling processes critical to bone homeostasis. We have identified that several cancer cell lines known to cause bone disruption in animal models of bone metastasis appear to secrete glutamate into their extracellular environment in vitro. Although these cells also express specific glutamate receptors, the implications of this potentially disruptive chemical signal are discussed in relation to normal glutamate-dependent communication processes in bone and a possible mechanistic connection is made between tumour cell glutamate release and the development of pathological changes in bone turnover.

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Section: Discussionmentioning

confidence: 99%

Cancer cell lines release glutamate into the extracellular environment

Seidlitz

Sharma

Saikali

et al. 2009

Clin Exp Metastasis

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“…26,27,31,34 The goal of the current study was to evaluate the efficacy of the glutamate release inhibitor riluzole and the NMDA receptor antagonist memantine in animal models of intracranial glioma and gliosarcoma. Although it is well known that riluzole and memantine cross the blood-brain barrier and reach appropriate concentrations for the therapy of neurodegenerative disorders such as ALS and Alzheimer’s disease, therapy with systemic riluzole or memantine in our models was ineffective.…”

Section: Discusssionmentioning

confidence: 99%

“…Toxic levels of glutamate associated with high-grade gliomas have been demonstrated both in vitro and in vivo. 4,27 Protection of the peritumoral functional, but possibly infiltrated, brain may indeed be beneficial for multiple reasons. Glutamate-mediated excitotoxicity to peritumoral astrocytes as well as neurons may contribute to decreased patient function due to the facilitation of peritumoral edema, direct cellular toxicity, and seizure activity.…”

Section: Discusssionmentioning

confidence: 99%

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Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

Yohay

Tyler²,

Weaver³

et al. 2014

JNS

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Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

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“…Recent reports showed that glutamate receptor antagonists inhibit cell proliferation of colon cancer, breast cancer, and lung cancer, and that the antiproliferative effect of the glutamate receptor antagonists is ascribed to their suppressive effect on cell division concomitant with an increase in cell death [9-11]. Nevertheless, due to their poor efficacy in penetrating the BBB, the glutamate receptor antagonists have had limited success in clinical applications to brain tumors [10]. …”

Section: Introductionmentioning

confidence: 99%

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

et al. 2014

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The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease.

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Glutamate antagonists limit tumor growth

Cited by 108 publications

References 42 publications

Cancer cell lines release glutamate into the extracellular environment

Cancer cell lines release glutamate into the extracellular environment

Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

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