AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group

Journal Article · Mon Aug 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.05.014· OSTI ID:21587811

Linlin, Zhong ^[1]; Honglin, Shen ^[2]; Chenfei, Huang ^[1]; Jing, Hongwu ^[3]

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1. Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794-9626 (United States)
2. Department of Pediatrics, The Affiliated Shenzhen Nanshan Hospital of Guangdong Medical College, 89 Taoyuan Road, Nanshan District, Shenzhen 518052 (China)
3. 670 Wiese Road, Cheshire, CT 06410 (United States)

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{sub max} of 837.42 {+-} 81.39 nmol/mg/min, K{sub m} of 9.317 {+-} 2.25 mM and k{sub cat}/K{sub m} of 3.24. AKR1B10 showed better catalytic efficiency toward idarubicin with V{sub max} at 460.23 {+-} 28.12 nmol/mg/min, K{sub m} at 0.461 {+-} 0.09 mM and k{sub cat}/K{sub 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 (50 nM) and idarubicin (30 nM) to corresponding alcohols. Within 24 h, approximately 20 {+-} 2.7% of daunorubicin (1 {mu}M) or 23 {+-} 2.3% of idarubicin (1 {mu}M) 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. - Highlights: > This study defines enzyme activity of AKR1B10 protein towards daunorubicin, idarubicin, doxorubicin, and epirubicin. > This study pinpoints the chemical group-C13 ketone that AKR1B10 acts on. > This study identifies that the C14 group (methyl or hydroxyl) affects the substrate specificity towards AKR1B10. > This study defines the role of AKR1B10 in cellular metabolism and pharmacokinetics of anthracyclines. > This study demonstrates the role of AKR1B10 in cell resistance to anthracyclines in an in vitro cell culture model.

• OSTI ID: 21587811
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.05.014; PII: S0041-008X(11)00193-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CELL CULTURES
DOXORUBICIN
ENZYME ACTIVITY
ENZYMES
FLUORESCENCE
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
IN VITRO
IONIZATION
LEUKEMIA
LIVER
LUNGS
LYMPHOMAS
MAMMARY GLANDS
MASS SPECTROSCOPY
METABOLISM
SUBSTRATES
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
ANTINEOPLASTIC DRUGS
BODY
CHROMATOGRAPHY
DIGESTIVE SYSTEM
DISEASES
DRUGS
EMISSION
GLANDS
IMMUNE SYSTEM DISEASES
LIQUID COLUMN CHROMATOGRAPHY
LUMINESCENCE
NEOPLASMS
ORGANIC COMPOUNDS
ORGANS
PHOTON EMISSION
PROTEINS
RESPIRATORY SYSTEM
SEPARATION PROCESSES
SPECTROSCOPY