SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

Robert, Stephanie M.; Buckingham, Susan; Campbell, Susan L.; Robel, Stefanie; Holt, Kenneth T.; Ogunrinu-Babarinde, Toyin; Warren, Paula; White, David M.; Reid, Meredith A.; Eschbacher, Jenny; Berens, Michael E.; Lahti, Adrienne C.; Nabors, L. Burt; Sontheimer, Harald

doi:10.1126/scitranslmed.aaa8103

Cited by 219 publications

(212 citation statements)

References 57 publications

Supporting

Mentioning

197

Contrasting

Unclassified

Order By: Relevance

“…Whether glioma patients with symptomatic epilepsy benefit with regard to OS has been a matter of debate [22,23,[33][34][35]. We found that AED treatment for epilepsy did not influence OS in the GBM subgroup.…”

Section: The Impact Of Epilepsy On Survivalmentioning

confidence: 62%

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

et al. 2016

View full text Add to dashboard Cite

Patients with glioblastoma (GBM) often suffer from symptomatic epilepsy. Older antiepileptic drugs (AEDs) which affect the enzyme system cytochrome P450 have been in extensive use, but there is an increasing focus on interactions with other drugs. This study investigated whether newer AEDs with little or no enzyme effect are increasingly preferred. Previous research has indicated that valproate improves survival in GBM. We investigated the impact of AEDs on overall survival in GBM patients. All GBM patients diagnosed in Norway 2004-2010 were included through a linkage of national registries, and follow-up data on the malignancy and drug usage were analyzed. In a multivariate cox proportional-hazards regression, AEDs were adjusted for each other and for relevant factors. Immortal time bias was eliminated with time-dependent variables. The study population was 1263 patients with histologically confirmed GBM. Carbamazepine was the most frequently prescribed AED to patients diagnosed with GBM during 2004-2006, while levetiracetam was increasingly prescribed to patients diagnosed later. Taking AEDs on a reimbursement code of epilepsy was not beneficial for survival. None of the six AEDs valproate, levetiracetam, carbamazepine, oxcarbazepine, lamotrigine or phenytoin significantly altered overall survival. There has been a shift in the prescriptions of AEDs to GBM patients from older to newer AEDs over time. We found no significant survival benefit in GBM patients neither from treatment with AEDs for epilepsy in general, nor from the usage of six separate AEDs.

show abstract

Section: The Impact Of Epilepsy On Survivalmentioning

confidence: 62%

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

et al. 2016

View full text Add to dashboard Cite

show abstract

“…However, an exacerbated activity of this antiporter may lead to glutamate excitotoxicity and neuronal death in ischemia (Soria et al, 2014). Also, higher expression of this subunit was found in glioma patients, and was associated with glutamate excitotoxicity, induced seizures and worse prognosis (Robert et al, 2015). Interestingly, there is a positive correlation between overexpression of Nrf2, tumor grade and reduced survival in patients with glioma (Zhao et al, 2015).…”

Section: Slc Transportersmentioning

confidence: 82%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

132

View full text Add to dashboard Cite

Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

show abstract

“…Indeed, strong xCT/ SLC7A11 expression in GBM patients correlated with an infiltrative phenotype on MRI and has been shown to be significantly associated with shorter progression-free and overall survival (34, 35). Microarray gene analysis of 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60) showed that SLC7A11 expression was negatively correlated with sensitivity of tumor cells to anti-cancer drugs (4).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of System xc− in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Polewski

Reveron-Thornton

Cherryholmes

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells up-regulate the expression of xCT (SLC7A11), the catalytic subunit of system xc−, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc− in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc− with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system xc− in glioma, stable SLC7A11 knock-down and over-expressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but over-expression did increase anchorage-independent cell growth. Knock-down of SLC7A11 increased basal ROS and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Over-expression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 over-expression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy. Implications: SLC7A11, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system xC− a potential therapeutic target in GBM.

show abstract

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

Cited by 219 publications

References 57 publications

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Increased Expression of System xc− in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Contact Info

Product

Resources

About