Document Detail

Pharmacogenomic approach reveals a role for the x(c)- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines.
MedLine Citation:
PMID:  20007406     Owner:  NLM     Status:  MEDLINE    
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.
Anh-Nhan Pham; Paul E Blower; Omar Alvarado; Ranadheer Ravula; Peter W Gout; Ying Huang
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Publication Detail:
Type:  Journal Article     Date:  2009-12-09
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  332     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-23     Completed Date:  2010-04-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  949-58     Citation Subset:  IM    
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
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MeSH Terms
Amino Acid Transport System y+ / biosynthesis,  genetics,  physiology*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cystine / metabolism
Drug Resistance, Neoplasm*
Gene Expression Profiling
Oligonucleotide Array Sequence Analysis
RNA, Small Interfering / genetics
Sulfasalazine / pharmacology
Triterpenes / pharmacology*
Reg. No./Substance:
0/Amino Acid Transport System y+; 0/Antineoplastic Agents; 0/RNA, Small Interfering; 0/SLC7A11 protein, human; 0/Triterpenes; 34157-83-0/tripterine; 56-89-3/Cystine; 599-79-1/Sulfasalazine

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