Document Detail


Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin.
MedLine Citation:
PMID:  20487225     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment. This study was performed to explore the reversal of MDR by doramectin from the avermectin family and nemadectin belonging to the milbemycin family.
METHODS: The MTT assay was used to evaluate the abilities of the two compounds to reverse drug resistance in adriamycin-resistant human breast carcinoma cells (MCF-7/adr). Intracellular accumulation of adriamycin was determined by HPLC. The effects of the two compounds on inhibiting P-glycoprotein (P-gp) efflux was demonstrated by accumulation of rhodamine 123 in MCF-7/adr cells. To investigate the mechanism of reversal by the two compounds, the expressions of P-gp and the MDR1 gene encoding P-gp were tested by flow cytometry and reverse-transcriptase PCR.
KEY FINDINGS: Doramectin and nemadectin at the high dose of 8 mumol/l significantly increased the sensitivity of MCF-7/adr cells to adriamycin by 49.35- and 23.97-fold, respectively. They also increased the intracellular accumulation of adriamycin and rhodamine 123 in MCF-7/adr cells in a dose-dependent manner. Expression of both P-gp and MDR1 were down-regulated.
CONCLUSIONS: Doramectin and nemadectin are promising agents for overcoming MDR in cancer therapy. Doramectin was more potent in reversing MDR.
Authors:
Aili Gao; Xiangjing Wang; Wensheng Xiang; Hongsheng Liang; Jiguo Gao; Yijun Yan
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  62     ISSN:  2042-7158     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-05-21     Completed Date:  2010-09-10     Revised Date:  2011-09-13    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  393-9     Citation Subset:  IM    
Affiliation:
School of Life Science, Northeast Agricultural University, Harbin, China.
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MeSH Terms
Descriptor/Qualifier:
Absorption / drug effects
Antibiotics, Antineoplastic / pharmacokinetics,  pharmacology*
Breast Neoplasms / drug therapy,  metabolism
Carcinoma / drug therapy,  metabolism
Cell Line, Tumor
Cell Survival / drug effects
Doxorubicin / pharmacokinetics
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Female
Gene Expression Regulation, Neoplastic / drug effects
Genes, MDR
Humans
Inhibitory Concentration 50
Ivermectin / analogs & derivatives*,  pharmacology
Macrolides / pharmacology*
P-Glycoprotein / genetics,  metabolism*
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Rhodamine 123 / pharmacokinetics
Chemical
Reg. No./Substance:
0/ABCB1 protein, human; 0/Antibiotics, Antineoplastic; 0/Macrolides; 0/P-Glycoprotein; 0/RNA, Messenger; 102130-84-7/nemadectin; 117704-25-3/doramectin; 23214-92-8/Doxorubicin; 62669-70-9/Rhodamine 123; 70288-86-7/Ivermectin

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


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