Document Detail


Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters.
MedLine Citation:
PMID:  18790787     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.
Authors:
Mitsunori Okabe; Gergely Szakács; Mark A Reimers; Toshihiro Suzuki; Matthew D Hall; Takaaki Abe; John N Weinstein; Michael M Gottesman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  7     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-15     Completed Date:  2008-10-22     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3081-91     Citation Subset:  IM    
Affiliation:
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / metabolism*
Cell Line, Tumor
Doxorubicin / chemistry,  metabolism,  pharmacology
Drug Screening Assays, Antitumor
Gene Expression Profiling*
Gene Expression Regulation, Neoplastic* / drug effects
Genes, Neoplasm*
Humans
Inhibitory Concentration 50
Mitoxantrone / chemistry,  metabolism,  pharmacology
Organic Anion Transporters / genetics*
Organic Cation Transport Proteins / genetics*,  metabolism
RNA, Messenger / genetics,  metabolism
Reproducibility of Results
Transfection
Grant Support
ID/Acronym/Agency:
Z01 BC007349-15/BC/NCI NIH HHS; Z01 BC010830-01/BC/NCI NIH HHS; Z01 BC010842-01/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Organic Anion Transporters; 0/Organic Cation Transport Proteins; 0/RNA, Messenger; 0/SLC22A4 protein, human; 23214-92-8/Doxorubicin; 65271-80-9/Mitoxantrone
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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