Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase--Carbonyl reductase 1.

Abstract

Curcumin is a major component of the plant Curcuma longa L. It is traditionally used as a spice and coloring in foods and is an important ingredient in curry. Curcuminoids have anti-oxidant and anti-inflammatory properties and gained increasing attention as potential neuroprotective and cancer preventive compounds. In the present study, we report that curcumin is a potent tight-binding inhibitor of human carbonyl reductase 1 (CBR1, Ki=223 nM). Curcumin acts as a non-competitive inhibitor with respect to the substrate 2,3-hexandione as revealed by plotting IC50-values against various substrate concentrations and most likely as a competitive inhibitor with respect to NADPH. Molecular modeling supports the finding that curcumin occupies the cofactor binding site of CBR1. Interestingly, CBR1 is one of the most effective human reductases in converting the anthracycline anti-tumor drug daunorubicin to daunorubicinol. The secondary alcohol metabolite daunorubicinol has significantly reduced anti-tumor activity and shows increased cardiotoxicity, thereby limiting the clinical use of daunorubicin. Thus, inhibition of CBR1 may increase the efficacy of daunorubicin in cancer tissue and simultaneously decrease its cardiotoxicity. Western-blots demonstrated basal expression of CBR1 in several cell lines. Significantly less daunorubicin reduction was detected after incubating A549 cell lysates with increasing concentrations of curcumin (up to 60% less with 50 μM curcumin), suggesting a beneficial effect in the co-treatment of anthracycline anti-tumor drugs together with curcumin.

• Authors: Jan Hintzpeter, Jan Hornung, Bettina Ebert, Hans-Jörg Martin, Edmund Maser
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 234 Pg. 162-8 (Jun 05 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 25541467 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• NADP
• Alcohol Oxidoreductases
• Aldo-Keto Reductases
• CBR1 protein, human
• Aldehyde Reductase
• Curcumin
• daunorubicinol
• Daunorubicin

Topics

• Alcohol Oxidoreductases (metabolism)
• Aldehyde Reductase (metabolism)
• Aldo-Keto Reductases
• Antineoplastic Agents (metabolism, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Curcumin (metabolism)
• Daunorubicin (analogs & derivatives, metabolism)
• Humans
• NADP (metabolism)
• Neoplasms (drug therapy, metabolism)