| The cyclin-dependent kinase inhibitor roscovitine and the nucleoside analog sangivamycin induce apoptosis in caspase-3 deficient breast cancer cells independent of caspase mediated P-glycoprotein cleavage: implications for therapy of drug resistant breast cancers. | |
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MedLine Citation:
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PMID: 19342873 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Resistance to multiple chemotherapeutic agents is a common clinical problem which can arise during cancer treatment. Drug resistance often involves overexpression of the multidrug resistance MDR1 gene, encoding P-glycoprotein (P-gp), a 170-kDa glycoprotein belonging to the ATP-binding cassette superfamily of membrane transporters. We have recently demonstrated apoptosis-induced, caspase-3-dependent P-gp cleavage in human T-lymphoblastoid CEM-R VBL100 cells. However, P-gp contain many aspartate residues which could be targeted by caspases other than caspase-3. To test whether other caspases could cleave P-gp in vivo, we investigated the fate of P-gp during roscovitine- and sangivamycin- induced apoptosis in MCF7 human breast cancer cells, as they lack functional caspase-3. MCF7 cells were stably transfected with human cDNA encoding P-gp. P-gp was cleaved in vitro by purified recombinant caspase-3, -6 and -7. However, P-gp cleavage was not detected in vivo in MCF7 cells induced to undergoing apoptosis by either roscovitine or sangivamycin, despite activation of both caspase-6 and -7. Interestingly, P-gp overexpressing MCF7 cells were more sensitive to either roscovitine or sangivamycin than wild-type cells, suggesting a novel potential therapeutic strategy against P-gp overexpressing cells. Taken together, our results support the concept that caspase-3 is the only caspase responsible for in vivo cleavage of P-gp and also highlight small molecules which could be effective in treating P-gp overexpressing cancers. |
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Authors:
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Alessandra Cappellini; Francesca Chiarini; Andrea Ognibene; James A McCubrey; Alberto M Martelli |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-05-02 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 8 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-04-22 Completed Date: 2009-06-03 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 1421-5 Citation Subset: IM |
Affiliation:
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Dipartimento di Scienze Motorie e della Salute, Università di Cassino, Cassino, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Breast Neoplasms / drug therapy*, enzymology, genetics Caspase 3 / metabolism* Cell Line, Tumor Cyclin-Dependent Kinases / antagonists & inhibitors* Drug Resistance, Neoplasm / drug effects Drug Screening Assays, Antitumor Gene Expression Regulation, Neoplastic / drug effects Humans Nucleosides / chemistry P-Glycoprotein / genetics, metabolism* Purines / pharmacology*, therapeutic use Pyrimidine Nucleosides / pharmacology*, therapeutic use RNA, Messenger / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01CA098195/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nucleosides; 0/P-Glycoprotein; 0/Purines; 0/Pyrimidine Nucleosides; 0/RNA, Messenger; 0/roscovitine; 18417-89-5/sangivamycin; EC 2.7.11.22/Cyclin-Dependent Kinases; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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