Reduction of doxorubicin and oracin and induction of carbonyl reductase in human breast carcinoma MCF-7 cells.

Abstract

In cancer cells, the drug-metabolizing enzymes may deactivate cytostatics, thus contributing to their survival. Moreover, the induction of these enzymes may also contribute to development of drug-resistance through acceleration of cytostatics deactivation. However, the principal metabolic pathways contributing to deactivation of many cytostatics still remain poorly defined. The main aims of the present study were: (i) to compare the reductive deactivation of cytostatic drugs doxorubicin (DOX) and oracin (ORC) in human breast cancer MCF-7 cells; (ii) to identify major enzyme(s) involved in the carbonyl reduction; and iii) to evaluate the activities and expression of selected carbonyl reducing enzymes in MCF-7 cells upon a short-term (48 h) exposure to either DOX or ORC. We found that MCF-7 cells were able to effectively metabolize both DOX and ORC through reduction of their carbonyl groups. The reduction of ORC was stereospecific, with a preferential formation of + enantiomer of dihydrooracin (DHO). The cytosolic carbonyl reductase CBR1 seemed to be a principal enzyme reducing both drugs, while cytosolic aldo-keto reductase AKR1C3 or microsomal reductases probably did not play important role in metabolism of either DOX or ORC. The exposure of MCF-7 cells to low (nanomolar) concentrations of DOX or ORC caused a significant elevation of reduction rates of both cytostatics, accompanied with an increase of CBR1 protein levels. Taken together, the present results seem to suggest that the accelerated metabolic deactivation of ORC or DOX might contribute to the survival of breast cancer cells during exposure to these cytostatics.

• Authors: Martina Gavelová, Jana Hladíková, Lenka Vildová, Romana Novotná, Jan Vondrácek, Pavel Krcmár, Miroslav Machala, Lenka Skálová
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 176 Issue 1 Pg. 9-18 (Oct 22 2008) ISSN: 0009-2797 [Print] Ireland
• PMID: 18755171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Ethanolamines
• Isoquinolines
• Methacrylates
• Phenylpropionates
• RNA, Messenger
• alpha-methylcinnamic acid
• oracine
• quercitrin
• Doxorubicin
• Quercetin
• 3-Hydroxysteroid Dehydrogenases
• Alcohol Oxidoreductases
• Aldo-Keto Reductases
• Hydroxyprostaglandin Dehydrogenases
• CBR1 protein, human
• Aldehyde Reductase
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3
• adriamycinol

Topics

• 3-Hydroxysteroid Dehydrogenases (antagonists & inhibitors, genetics, metabolism)
• Alcohol Oxidoreductases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Aldehyde Reductase
• Aldo-Keto Reductase Family 1 Member C3
• Aldo-Keto Reductases
• Biotransformation (drug effects)
• Blotting, Western
• Breast Neoplasms (enzymology, genetics)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Doxorubicin (analogs & derivatives, chemistry, metabolism, pharmacology)
• Enzyme Induction (drug effects)
• Enzyme Inhibitors (pharmacology)
• Ethanolamines (chemistry, metabolism, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydroxyprostaglandin Dehydrogenases (antagonists & inhibitors, genetics, metabolism)
• Isoquinolines (chemistry, metabolism, pharmacology)
• Kinetics
• Methacrylates (pharmacology)
• Oxidation-Reduction (drug effects)
• Phenylpropionates (pharmacology)
• Quercetin (analogs & derivatives, pharmacology)
• RNA, Messenger (genetics, metabolism)
• Subcellular Fractions (drug effects, metabolism)