Document Detail


The effectiveness of oracin in enhancing the cytotoxicity of doxorubicin through the inhibition of doxorubicin deactivation in breast cancer MCF7 cells.
MedLine Citation:
PMID:  20698750     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The maximal therapeutic doses of the cytostatic drug doxorubicin (DOX) are strictly limited by the development of systemic toxicity, especially cardiotoxicity. The inhibition of DOX-metabolizing enzymes within cancer cells is possible strategy to improve DOX efficacy. In breast cancer cells (MCF7), DOX is effectively deactivated by carbonyl reduction. The aim of the present study was to test whether isoquinoline derivative oracin (ORC) is able to inhibit DOX reductases and to enhance DOX cytotoxic efficacy. The kinetics studies of DOX reduction in MCF7 cytosolic fractions were evaluated using high-performance liquid chromatography. The cytotoxicity of DOX, ORC, and DOX+ORC combinations was assayed using cell-viability tests and caspases activities and monitored using xCELLigence System for real-time cell analysis. ORC significantly inhibited DOX reduction in MCF7 cytosol. Competitive inhibition was found. The viability was significantly lower in cells treated with ORC+DOX combinations in comparison to cells treated with DOX alone. Significant enhancement of DOX cytotoxicity was achieved already with 0.5 µM ORC. DOX together with ORC was able to kill about 55% cells more than DOX alone. ORC significantly increases DOX efficacy in MCF7 cells probably due to the inhibition of DOX reductases.
Authors:
V Hanusová; V Králová; L Schröterová; L Trilecová; A Pakostová; L Skálová
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Xenobiotica; the fate of foreign compounds in biological systems     Volume:  40     ISSN:  1366-5928     ISO Abbreviation:  Xenobiotica     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-14     Completed Date:  2011-01-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1306665     Medline TA:  Xenobiotica     Country:  England    
Other Details:
Languages:  eng     Pagination:  681-90     Citation Subset:  IM    
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / metabolism,  pharmacology*
Caspases / metabolism
Cell Line, Tumor
Doxorubicin / metabolism,  pharmacology*
Electric Impedance
Ethanolamines / pharmacology*
Humans
Isoquinolines / pharmacology*
Oxidoreductases / antagonists & inhibitors*,  metabolism
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Ethanolamines; 0/Isoquinolines; 148317-76-4/oracine; 23214-92-8/Doxorubicin; EC 1.-/Oxidoreductases; EC 3.4.22.-/Caspases

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


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