| AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. | |
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MedLine Citation:
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PMID: 21640744 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Daunorubicin, idarubicin, doxorubicin and epirubicin are anthracyclines widely used for the treatment of lymphoma, leukemia, and breast, lung, and liver cancers, but tumor resistance limits their clinical success. Aldo-keto reductase family 1 B10 (AKR1B10) is an NADPH-dependent enzyme overexpressed in liver and lung carcinomas. This study was aimed to determine the role of AKR1B10 in tumor resistance to anthracyclines. AKR1B10 activity toward anthracyclines was measured using recombinant protein. Cell resistance to anthracycline was determined by ectopic expression of AKR1B10 or inhibition by epalrestat. Results showed that AKR1B10 reduces C13-ketonic group on side chain of daunorubicin and idarubicin to hydroxyl forms. In vitro, AKR1B10 converted daunorubicin to daunorubicinol at V(max) of 837.42±81.39nmol/mg/min, K(m) of 9.317±2.25mM and k(cat)/K(m) of 3.24. AKR1B10 showed better catalytic efficiency toward idarubicin with V(max) at 460.23±28.12nmol/mg/min, K(m) at 0.461±0.09mM and k(cat)/K(m) at 35.94. AKR1B10 was less active toward doxorubicin and epirubicin with a C14-hydroxyl group. In living cells, AKR1B10 efficiently catalyzed reduction of daunorubicin (50nM) and idarubicin (30nM) to corresponding alcohols. Within 24h, approximately 20±2.7% of daunorubicin (1μM) or 23±2.3% of idarubicin (1μM) was converted to daunorubicinol or idarubicinol in AKR1B10 expression cells compared to 7±0.9% and 5±1.5% in vector control. AKR1B10 expression led to cell resistance to daunorubicin and idarubicin, but inhibitor epalrestat showed a synergistic role with these agents. Together our data suggest that AKR1B10 participates in cellular metabolism of daunorubicin and idarubicin, resulting in drug resistance. These data are informative for the clinical use of idarubicin and daunorubicin. |
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Authors:
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Linlin Zhong; Honglin Shen; Chenfei Huang; Hongwu Jing; Deliang Cao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-05-26 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 255 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-01 Completed Date: 2011-09-29 Revised Date: 2012-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 40-7 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Medical Microbiology, Immunology, & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794-9626, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Reductase
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physiology* Antibiotics, Antineoplastic / pharmacology* Cells, Cultured Daunorubicin / metabolism, pharmacology* Drug Resistance, Neoplasm Humans Idarubicin / metabolism, pharmacology* Ketones / chemistry Oxidation-Reduction |
| Grant Support | |
ID/Acronym/Agency:
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CA122327/CA/NCI NIH HHS; R21 CA122327-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Ketones; 20830-81-3/Daunorubicin; 58957-92-9/Idarubicin; EC 1.1.1.-/AKR1B10 protein, human; EC 1.1.1.21/Aldehyde Reductase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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