| Inhibition of glutathione synthesis overcomes Bcl-2-mediated topoisomerase inhibitor resistance and induces nonapoptotic cell death via mitochondrial-independent pathway. | |
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MedLine Citation:
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PMID: 16740716 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Akira Yoshida; Haruyuki Takemura; Hitoshi Inoue; Toshiyuki Miyashita; Takanori Ueda |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 66 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-06-02 Completed Date: 2006-07-27 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 5772-80 Citation Subset: IM |
Affiliation:
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First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. ayoshi@fmsrsa.fukui-med.ac.jp |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Combined Chemotherapy Protocols
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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* Humans 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 |
| Chemical | |
Reg. No./Substance:
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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 5.99.1.2/DNA Topoisomerases, Type I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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