Document Detail


Targeted delivery of doxorubicin through conjugation with EGF receptor-binding peptide overcomes drug resistance in human colon cancer cells.
MedLine Citation:
PMID:  23146125     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Induction of multidrug resistance by doxorubicin (DOX), together with non-specific toxicities, has restricted DOX-based chemotherapy. Recently, we demonstrated that DOX conjugated with an EGF receptor-binding peptide (DOX-EBP) had enhanced anticancer efficacy and reduced systemic toxicity when targeting EGF receptor-overexpressing tumours. Here we investigated whether DOX-EBP is able to overcome drug resistance and the underlying molecular mechanisms.
EXPERIMENTAL APPROACH: DOX-resistant SW480/DOX cells were derived from non-resistant SW480 cells by stepwise exposure to increasing concentrations of DOX, and P-glycoprotein overexpression induced by DOX was confirmed by Western blotting. Cytotoxicity and intracellular distribution of drugs were evaluated by MTT assay and fluorescence microscopy respectively. EGF receptor-mediated endocytosis was determined in EGF receptor and endocytosis inhibition assays. Drug accumulation in tumour cells and murine xenografts was determined by HPLC.
KEY RESULTS: The cytotoxicity and accumulation of DOX-EBP in SW480/DOX cells were almost the same as in SW480 cells, but those of free DOX were reduced. DOX-EBP accumulation was prevented by inhibitors of both EGF receptors and endocytosis, suggesting EGF receptors mediate endocytotic uptake. Tumour accumulation of DOX-EBP was significantly higher than free DOX in mice, and the levels of DOX-EBP were similar in DOX-resistant and non-resistant tumour tissues. Importantly, DOX-EBP, but not free DOX, was effective at inhibiting solid tumour growth and increased survival rate in both sensitive and resistant models.
CONCLUSION AND IMPLICATIONS: DOX-EBP can overcome DOX resistance of tumour cells and increase in vivo antitumour efficacy. Therefore, it has the potential to be a potent therapeutic agent for treating drug-resistant cancers.
Authors:
Shibin Ai; Tao Jia; Weilun Ai; Jianli Duan; Yongmei Liu; Jing Chen; Xin Liu; Fan Yang; Yuan Tian; Zebo Huang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1719-35     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / chemistry,  pharmacology*
Cell Line, Tumor
Colonic Neoplasms / drug therapy,  metabolism,  pathology
Doxorubicin / chemistry,  pharmacology*
Drug Delivery Systems
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Endocytosis
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Oligopeptides / chemistry*
P-Glycoprotein / metabolism
Receptor, Epidermal Growth Factor / metabolism*
Transplantation, Heterologous
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Oligopeptides; 0/P-Glycoprotein; 80168379AG/Doxorubicin; EC 2.7.10.1/Receptor, Epidermal Growth Factor
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