Document Detail


Separate roles for the Golgi apparatus and lysosomes in the sequestration of drugs in the multidrug-resistant human leukemic cell line HL-60.
MedLine Citation:
PMID:  14522995     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yuping Gong; Muralikrishna Duvvuri; Jeffrey P Krise
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Publication Detail:
Type:  Journal Article     Date:  2003-09-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-08     Completed Date:  2004-01-15     Revised Date:  2006-06-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  50234-9     Citation Subset:  IM    
Affiliation:
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / 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:
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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