Document Detail

Inhibition of glutathione synthesis overcomes Bcl-2-mediated topoisomerase inhibitor resistance and induces nonapoptotic cell death via mitochondrial-independent pathway.
MedLine Citation:
PMID:  16740716     Owner:  NLM     Status:  MEDLINE    
Bcl-2 protein plays a critical role in inhibiting anticancer drug-induced apoptosis. We found that Bcl-2 overexpression is associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after treatment with etoposide or SN-38, a derivative of camptothecin, in leukemia 697 cells with wild-type p53. Treatment of Bcl-2-overexpressing 697 cells (697-Bcl-2) with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, reduced cellular glutathione levels and completely abolished Bcl-2-mediated drug resistance. Morphologic studies revealed that nonapoptotic cell death was induced in 697-Bcl-2 cells after treatment with BSO plus etoposide or SN-38. Activation of caspase-3/7 and cytochrome c release could not be detected in 697-Bcl-2 cells after these drug treatments. Notably, we showed that proteasome-mediated down-regulation of Puma and Noxa proteins occurs in 697-Bcl-2 cells after treatment with BSO plus topoisomerase inhibitor, although there is an increase in the protein levels of p53 in these 697-Bcl-2 cells. In contrast, parental 697 cells underwent typical apoptosis with up-regulation of Puma and Noxa proteins, followed by cytochrome c release and caspase-3/7 activation after treatment with topoisomerase inhibitor in the presence or absence of BSO. Our data suggest that BSO may possess a unique activity to overcome Bcl-2-mediated drug resistance by stimulating the signals that can bypass mitochondrial process in Bcl-2-overexpressing cells.
Akira Yoshida; Haruyuki Takemura; Hitoshi Inoue; Toshiyuki Miyashita; Takanori Ueda
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-06-02     Completed Date:  2006-07-27     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5772-80     Citation Subset:  IM    
First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis Regulatory Proteins / biosynthesis,  genetics
Buthionine Sulfoximine / administration & dosage,  pharmacology
Camptothecin / administration & dosage,  analogs & derivatives,  pharmacology
Caspase 3
Caspase 7
Caspases / metabolism
Cell Death / drug effects,  physiology
Cell Line, Tumor
DNA Topoisomerases, Type I / antagonists & inhibitors*,  metabolism
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Enzyme Activation
Etoposide / administration & dosage,  pharmacology
Gene Expression Regulation, Leukemic / drug effects
Glutathione / antagonists & inhibitors*,  biosynthesis*
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*,  enzymology,  metabolism*,  pathology
Proto-Oncogene Proteins / biosynthesis,  genetics
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  biosynthesis,  genetics,  metabolism*
Tumor Suppressor Protein p53 / biosynthesis,  genetics
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 100286-90-6/irinotecan; 33419-42-0/Etoposide; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; 7689-03-4/Camptothecin; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP7 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspases; EC Topoisomerases, Type I

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