daunorubicinol and Neoplasms

1. ABCB1 (P-glycoprotein, MDR1) is one of the most important transporter involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Several intracellular enzymes metabolise anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolite efflux by ABCB1 transporter is not well characterised, while it may be the mechanism responsible for the metabolites' lack of activity.2. In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modelling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux.3. Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 significantly affected the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicinol accumulation were influenced by the activity of ABCB1 modulator - valspodar.4. Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. Therefore crosstalk between the process of anthracyclines metabolism and metabolite efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.

Topics: Adenosine Triphosphatases; Anthracyclines; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Daunorubicin; Doxorubicin; Humans; Neoplasms

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.

Topics: Alcohol Oxidoreductases; Aldehyde Reductase; Aldo-Keto Reductases; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Curcumin; Daunorubicin; Humans; NADP; Neoplasms

The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS.. Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression.. CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts.. CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.

Topics: 3-Hydroxysteroid Dehydrogenases; Alcohol Oxidoreductases; Aldehyde Reductase; Aldo-Keto Reductase Family 1 Member C3; Anthracyclines; Cardiotoxins; Daunorubicin; Down Syndrome; Female; Gene Expression; Genotype; Heart; Humans; Hydroxyprostaglandin Dehydrogenases; Male; Myocardium; Neoplasms; RNA, Messenger

We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.. Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95% for age or as body fat >30%. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.. A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h ± 14% and 68.1 L/m(2) ± 24%, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h ± 5.6% and 232 L/m(2) ± 10%, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.. We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.

Topics: Absorptiometry, Photon; Antibiotics, Antineoplastic; Body Composition; Body Mass Index; Child; Daunorubicin; Drug Screening Assays, Antitumor; Female; Genome-Wide Association Study; Glutathione S-Transferase pi; Haplotypes; Humans; Male; Metabolic Clearance Rate; Models, Statistical; Neoplasms; Obesity; Oxygenases; Pharmacogenetics; Polymorphism, Genetic

Topics: Animals; Bile; Chromatography, High Pressure Liquid; Daunorubicin; Drug Evaluation; Humans; Kinetics; Neoplasms; Rats; Rats, Inbred Strains