| Separate roles for the Golgi apparatus and lysosomes in the sequestration of drugs in the multidrug-resistant human leukemic cell line HL-60. | |
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MedLine Citation:
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PMID: 14522995 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The sequestration of drugs away from cellular target sites into cytoplasmic organelles of multidrug-resistant (MDR) cancer cells has been recently shown to be a cause for ineffective drug therapy. This process is poorly understood despite the fact that it has been observed in a large number of MDR cancer cell lines. Analysis of drug sequestration in these cells has traditionally been done using fluorescent anthracycline antibiotics (i.e. daunorubicin, doxorubicin). This narrow selection of substrates has resulted in a limited understanding of sequestration mechanisms and the intracellular compartments that are involved. To better characterize this phenotype, we chose to examine the sequestration of molecules having different acid/base properties in the MDR HL-60 human leukemic cell line. Here we show that weakly basic drug daunorubicin is sequestered into lysosomes according to a pH partitioning type mechanism, whereas sulforhodamime 101, a zwitterionic molecule, is sequestered into the Golgi apparatus through a drug transporter-mediated process. Quantitative intracellular pH measurements reveal that the lysosome-tocytosol pH gradient is expanded in the MDR line. Moreover, the MDR cells overexpress the multidrug resistance-related protein (MRP1), which is localized to the Golgi apparatus. These results demonstrate, for the first time, that two distinct mechanisms for intracellular compartmentalization are operational in a single MDR cell line. |
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Authors:
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Yuping Gong; Muralikrishna Duvvuri; Jeffrey P Krise |
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Publication Detail:
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Type: Journal Article Date: 2003-09-30 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 278 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2003 Dec |
Date Detail:
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Created Date: 2003-12-08 Completed Date: 2004-01-15 Revised Date: 2006-06-20 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 50234-9 Citation Subset: IM |
Affiliation:
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Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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pharmacology Antineoplastic Agents / pharmacology Biological Transport Cell Line Cell Membrane / metabolism Chemokines, CC / metabolism Coloring Agents / pharmacology Daunorubicin / metabolism, pharmacology Drug Resistance, Neoplasm* Golgi Apparatus / metabolism, physiology* HL-60 Cells Humans Hydrogen-Ion Concentration Inhibitory Concentration 50 Lysosomes / metabolism, physiology* Microscopy, Fluorescence Phenotype Rhodamines / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/Chemokines, CC; 0/Coloring Agents; 0/Rhodamines; 139568-96-0/Ccl6 protein, mouse; 20830-81-3/Daunorubicin; 60311-02-6/sulforhodamine 101 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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