Linked Life Data

20007406

Source:http://linkedlifedata.com/resource/pubmed/id/20007406

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2010-2-23
pubmed:abstractText
The x(c)(-) cystine/glutamate antiporter has been implicated in GSH-based chemoresistance because it mediates cellular uptake of cystine/cysteine for sustenance of intracellular GSH levels. Celastrol, isolated from a Chinese medicinal herb, is a novel heat shock protein 90 (Hsp90) inhibitor with potent anticancer activity against glioma in vitro and in vivo. In search of correlations between growth-inhibitory potency of celastrol in NCI-60 cell lines and microarray expression profiles of most known transporters, we found that expression of SLC7A11, the gene encoding the light chain subunit of x(c)(-), showed a strong negative correlation with celastrol activity. This novel gene-drug correlation was validated. In celastrol-resistant glioma cells that highly expressed SLC7A11, sensitivity to celastrol was consistently increased via treatment with x(c)(-) inhibitors, including glutamate, (S)-4-carboxyphenylglycine, sulfasalazine, and SLC7A11 small interfering RNA. The GSH synthesis inhibitor, buthionine sulfoximine, also increased celastrol sensitivity, whereas the GSH booster, N-acetylcysteine, suppressed its cytotoxicity. Furthermore, the glioma cell lines were dependent on x(c)(-)-mediated cystine uptake for viability, because cystine omission from the culture medium resulted in cell death and treatment with sulfasalazine depleted GSH levels and inhibited their growth. Combined treatment of glioma cells with sulfasalazine and celastrol led to chemosensitization, as suggested by increased celastrol-induced cell cycle arrest, apoptosis, and down-regulation of the Hsp90 client protein, epidermal growth factor receptor. These results indicate that the x(c)(-) transporter provides a useful target for glioma therapy. x(c)(-) inhibitors such as sulfasalazine, a Food and Drug Administration-approved drug, may be effective both as an anticancer drug and as an agent for sensitizing gliomas to celastrol.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
332
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
949-58
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Pharmacogenomic approach reveals a role for the x(c)- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines.
pubmed:affiliation
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
pubmed:publicationType
Journal Article