Inhibition of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.gif" overflow="scroll"><mml:mrow><mml:mmultiscripts><mml:mrow><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mtext>c</mml:mtext></mml:mrow><mml:none /><mml:none /><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:mmultiscripts></mml:mrow></mml:math> transporter-mediated cystine uptake by sulfasalazine analogs

Shukla, Krupa H.; Thomas, Ajit G.; Ferraris, Dana; Hin, Niyada; Sattler, Rita; Alt, Jesse; Rojas, Camilo; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1016/j.bmcl.2011.07.081

Cited by 37 publications

(36 citation statements)

References 19 publications

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“…Oxidizing agents like H 2 O 2 are reported to induce increases in Xc − transporter levels, resulting in increased intracellular cysteine and consequently increased GSH synthesis [23]. Xc − transporter inhibitors (e.g., sulfasalazine and analogs) have the opposite effect, blocking import of cystine and resulting in limited GSH synthesis [54,55]. …”

Section: Experimental Manipulation Of Cellular Gsh Contentmentioning

confidence: 99%

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

2012

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Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

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Section: Experimental Manipulation Of Cellular Gsh Contentmentioning

confidence: 99%

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

2012

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“…While some progress has been made toward developing more potent compounds based on the SAS scaffold (Shukla et al, 2011), the identification of system x c − inhibitors based on alternative scaffolds remains a pressing need and would be useful to test the hypothesis that system x c − inhibition is therapeutically beneficial in glioma and other contexts. We previously demonstrated that the small molecule erastin prevents Na + -independent cystine uptake (Dixon et al, 2012), suggesting that erastin may inhibit system x c − function and represent a novel scaffold targeting this transport system.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

Dixon

Patel

Welsch

et al. 2014

eLife

1,580

1,361

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Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc− is implicated in numerous pathologies. Pharmacological agents that inhibit system xc− activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system xc−. RNA sequencing revealed that inhibition of cystine–glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1, providing a pharmacodynamic marker for system xc− inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc− function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis.DOI: http://dx.doi.org/10.7554/eLife.02523.001

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“…One FDA-approved SXC inhibitor already exists (sulfasalazine(19)), and others are being developed(20). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Glioma is the most common malignant primary brain tumor. Their rapid growth is aided by tumor-mediated release of glutamate, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc− (SXC), responsible for the cellular synthesis of glutathione. However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient tissue and tissues propagated in mice, we found that approximately 50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to annotated genomic data in the REMBRANDT database. In a clinical pilot study we used Magnetic Resonance Spectroscopy (MRS) to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the FDA-approved SXC inhibitor, sulfasalazine. In 9 glioma patients with biopsy-confirmed expression of SXC, we found that its expression positively correlates with glutamate release, which is acutely inhibited with oral sulfasalazine. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and peritumoral seizures.

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Inhibition of xc- transporter-mediated cystine uptake by sulfasalazine analogs

Cited by 37 publications

References 19 publications

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

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

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