Document Detail


Reduction of doxorubicin resistance in P-glycoprotein overexpressing cells by hybrid cell-penetrating and drug-binding peptide.
MedLine Citation:
PMID:  20088680     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Drug efflux by the membrane transporter P-glycoprotein (P-gp) plays a key role in multidrug resistance (MDR). In order to bypass P-gp, thus overcoming MDR, a hybrid peptide comprising a cell penetrating peptide (Tat) and a drug binding motif (DBM) has been developed to noncovalently bind and deliver doxorubicin (Dox) into MDR cells. The uptake of Dox into the leukemia cell line K562 and its P-gp overexpressing subline KD30 increased in the presence of DBM-Tat peptide. Confocal microscopy indicated that DBM-Tat associated Dox was directed to a perinuclear area of KD30 cells, while this was not observed in parent K562 cells. When KD30 cells were pretreated with the endosomotropic agent chloroquine (CLQ), peptide associated Dox redistributed into the cytosol, indicating that endocytosis was the predominant uptake route. Altered drug uptake kinetics observed by cellular accumulation assay also supported an endocytic uptake. In the presence of CLQ, DBM-Tat was able to enhance the cytotoxicity of Dox by 68.4% at 5 microM peptide concentration in KD30 cells but there were only minor effects on Dox cytotoxicity in K562 cells even in the presence of CLQ. Thus, combining Dox with DBM-Tat reduces P-gp mediated drug efflux, without a requirement for drug modification or inhibiting P-gp function.
Authors:
Zhaohua Zheng; Harmesh Aojula; David Clarke
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of drug targeting     Volume:  18     ISSN:  1029-2330     ISO Abbreviation:  J Drug Target     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-10     Completed Date:  2010-10-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9312476     Medline TA:  J Drug Target     Country:  England    
Other Details:
Languages:  eng     Pagination:  477-87     Citation Subset:  IM    
Affiliation:
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Stopford Building, Oxford Road, Manchester, UK. joyce.zheng@gmail.com
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / administration & dosage,  pharmacokinetics,  pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Doxorubicin / administration & dosage,  pharmacokinetics,  pharmacology*
Drug Carriers / chemistry*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Flow Cytometry
Humans
K562 Cells
Microscopy, Confocal
P-Glycoprotein / biosynthesis*
Peptide Fragments / chemistry*
Permeability
Solubility
Spectrometry, Fluorescence
tat Gene Products, Human Immunodeficiency Virus / chemistry*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Drug Carriers; 0/P-Glycoprotein; 0/Peptide Fragments; 0/tat Gene Products, Human Immunodeficiency Virus; 0/tat peptide (49-57), Human immunodeficiency virus 1; 23214-92-8/Doxorubicin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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