Document Detail


Selective inhibition of P-glycoprotein expression in multidrug-resistant tumor cells by a designed transcriptional regulator.
MedLine Citation:
PMID:  12183653     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Selective inhibition of the multidrug resistance 1 (MDR1) gene and its product, the P-glycoprotein, a membrane transporter responsible for multidrug resistance, could be an important approach for enhancing cancer therapeutics. An emerging strategy for selective gene regulation involves designed zinc finger proteins that can recognize specific sequences in the promoter regions of disease-related genes. Herein, we investigate the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells displaying ponasterone-inducible expression of a designed transcriptional repressor targeted to the MDR1 promoter. The controlled production of this novel repressor resulted in major reductions in P-glycoprotein levels in these otherwise highly drug-resistant tumor cells. The regulated reduction of MDR1 expression in NCI/ADR-RES cells was accompanied by a marked increase in the rate of uptake of the P-glycoprotein substrate rhodamine 123. In addition, the cytotoxicity profile of the antitumor drug doxorubicin was dramatically altered in the induced cells compared with controls. The expression levels of other genes were examined both by a DNA array analysis of approximately 2000 genes and by biochemical techniques. Although some changes were observed in mRNA levels of nontargeted genes, the most dramatic effect by far was on MDR1, indicating that the action of the designed transcriptional repressor was quite selective. This study suggests that designed transcriptional regulators can be used to strongly and selectively influence expression of cancer-related genes, even under circumstances of extensive amplification of the target gene.
Authors:
Dong Xu; Dongjiu Ye; Michael Fisher; R L Juliano
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  302     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-08-16     Completed Date:  2002-09-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  963-71     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 29799, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology
Antineoplastic Agents / pharmacology
Blotting, Northern
Blotting, Western
Doxorubicin / pharmacology
Flow Cytometry
Fluorescent Dyes
Gene Expression Regulation, Neoplastic / genetics*
Genes, MDR / genetics*
Humans
Oligonucleotide Array Sequence Analysis
P-Glycoproteins / antagonists & inhibitors*,  biosynthesis*
Plasmids / genetics
RNA, Neoplasm / biosynthesis,  genetics
Repressor Proteins / biosynthesis,  genetics
Rhodamine 123
Transfection
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
P01 GM 59299/GM/NIGMS NIH HHS; R01 CA 77340/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/Fluorescent Dyes; 0/P-Glycoproteins; 0/RNA, Neoplasm; 0/Repressor Proteins; 23214-92-8/Doxorubicin; 62669-70-9/Rhodamine 123

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


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