The influence of oracin on reduction and toxicity of doxorubicin in hepatocytes and mammary epithelial cells MCF-10A.
The ways, how to increase effectiveness of doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells, have been intensively studied. In breast cancer cells MCF-7, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased DOX antiproliferative effect. The aim of this study was to test the influence of ORC on the reduction of DOX and its toxicity in hepatocytes and non-tumourous breast cells.        The kinetics of DOX reduction was measured in cytosols from rat liver, human liver and human mammary epithelial cells MCF-10A. Activity and expression of carbonyl reductase 1 (CBR1) were assayed using menadione as a substrate and western blot analysis. End-point tests of viability served for study of cytotoxicity of DOX, ORC and DOX+ORC combinations in rat hepatocytes and MCF-10A cells.        The inhibitory effect of ORC on DOX reductases was almost none in MCF-10A cells and mild in liver. CBR1 expression and activity was lower in non-tumourous MCF-10A cells than in cancer MCF-7 cells. Cytotoxicity tests showed that DOX+ORC combinations had significantly lower toxicity than DOX alone in MCF-10A cells as well as in hepatocytes.        ORC significantly decreases DOX toxicity in MCF-10A and in hepatocytes. Therefore, concomitant use of ORC and DOX may protect normal cells against DOX toxicity.
Department of Biochemical Sciences, Charles University, Hradec Králové, Czech Republic.
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Hanušová
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Boušová
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Pakostová
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Skálová
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D004317:Doxorubicin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008099:Liver / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar
D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human