Document Detail


Lack of correlation of MRP and gamma-glutamylcysteine synthetase overexpression with doxorubicin resistance due to increased apoptosis in SV40 large T-antigen-transformed human mesothelial cells.
MedLine Citation:
PMID:  9788569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Evidence suggests that viral proteins such as simian virus large T-antigen (SV40 TAg) play a role in the response of cancer cells to chemotherapeutic agents. In this study, we investigated whether SV40 TAg-immortalized human mesothelial cells express drug resistance-related proteins and display resistance to chemotherapy, and whether SV40 TAg transformation affects apoptosis. METHODS: We determined the mRNA and protein levels of the multidrug resistance-associated protein (MRP), gamma-glutamylcysteine synthetase heavy subunit (gamma-GCSh), and P-glycoprotein (product of the MDR1 gene) by RT-PCR and Western blotting, respectively, in normal human mesothelial (NHM) cell and SV40 TAg-transformed human mesothelial (Met-5A) cells. The effect of increasing concentrations of doxorubicin (DOX) on these cells was investigated using an MTT cytotoxicity assay, and the glutathione (GSH) content was measured spectrophotometrically. DOX accumulation in these cells was measured by treating the cells with [14C]DOX followed by scintillation counting. Cytoplasmic bNA fragmentation due to apoptosis following DOX treatment of the cells was quantitated by ELISA. RESULTS: We showed that the MRP and gamma-GCSh genes, but not MDR1, are coordinately overexpressed in Met-5A cells compared with NHM cells. Expression of MRP protein as detected by an anti-MRP antibody correlated with increased GSH levels and decreased accumulation of [14C]DOX in Met-5A cells compared with NHM cells. However, Met-5A cells were twofold more sensitive to DOX than NHM cells. In addition, quantitative measurement of apoptosis when cells were treated with 0.05 and 0.5 microM DOX revealed that drug-induced apoptotic cell death was increased about 1.4- and 3.0-fold, respectively, in Met-5A cells compared with NHM cells. CONCLUSIONS: These results suggest that increased levels of apoptosis might help overcome the DOX resistance effects of MRP/gamma-GCSh overexpression in SV40 TAg-transformed Met-5A cells.
Authors:
B Ogretmen; H Bahadori; M McCauley; A Boylan; M Green; A R Safa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  42     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  1998  
Date Detail:
Created Date:  1998-11-04     Completed Date:  1998-11-04     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  441-6     Citation Subset:  IM    
Affiliation:
Department of Experimental Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston 29425, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics*
Antigens, Polyomavirus Transforming
Apoptosis*
Base Sequence
Cell Line, Transformed
DNA Primers
Doxorubicin / pharmacology*
Drug Resistance, Multiple / genetics
Drug Resistance, Neoplasm / genetics
Epithelium / drug effects
Glutamate-Cysteine Ligase / genetics*
Glutathione / metabolism
Humans
Multidrug Resistance-Associated Proteins
RNA, Messenger / genetics
Simian virus 40 / immunology
Grant Support
ID/Acronym/Agency:
CA 56078/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Antigens, Polyomavirus Transforming; 0/DNA Primers; 0/Multidrug Resistance-Associated Proteins; 0/RNA, Messenger; 23214-92-8/Doxorubicin; 70-18-8/Glutathione; EC 6.3.2.2/Glutamate-Cysteine Ligase

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


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