title: 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.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswikerstr. 10, D-24105 Kiel, Germany. Electronic address: hintzpeter@tox.uni-kiel.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Hintzpeter
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswikerstr. 10, D-24105 Kiel, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hornung
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswikerstr. 10, D-24105 Kiel, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Ebert
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswikerstr. 10, D-24105 Kiel, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Martin
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswikerstr. 10, D-24105 Kiel, Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000449:Aldehyde Reductase / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003474:Curcumin / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009249:NADP; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; C531129:CBR1 protein, human; D000449:Aldehyde Reductase; D003474:Curcumin; C000847:daunorubicinol; D003630:Daunorubicin
keywords: Anthracycline resistance; Carbonyl reductase 1; Cardiotoxicity; Curcumin; Daunorubicin; Tight-binding inhibition