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Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors with and Without Down Syndrome

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Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors with and Without Down Syndrome Pharm Res DOI 10.1007/s11095-013-1267-1 RESEARCH PAPER Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome Adolfo Quiñones-Lombraña & Daniel Ferguson & Rachael Hageman Blair & James L. Kalabus & Almedina Redzematovic & Javier G. Blanco Received: 16 September 2013 /Accepted: 9 December 2013 # Springer Science+Business Media New York 2014 ABSTRACT CBR1 rs9024 genotype status impacts on cardiac CBR1 expres- Purpose The intracardiac synthesis of anthracycline alcohol sion in non-DS hearts. metabolites (e.g., daunorubicinol) contributes to the patho- Conclusions CBR1, AKR1A1, and AKR7A2 protein levels point genesis of anthracycline-related cardiotoxicity. Cancer pa- to be important determinants for predicting the synthesis of tients with Down syndrome (DS) are at increased risk for cardiotoxic daunorubicinol in heart. anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- KEY WORDS Aldo-keto reductases . Anthracycline-related and without- DS. cardiotoxicity . Anthracyclines . Carbonyl reductases . Down Methods Cardiac expression of CBR1, CBR3, AKR1A1, syndrome AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays ABBREVIATIONS using daunorubicin. The CBR1 polymorphism rs9024 was inves- aCGH Array comparative genomic hybridization tigated by allelic discrimination with fluorescent probes. The ACTB Actin B contribution of CBRs/AKRs proteins to daunorubicin reductase AKR1A1 Aldo-keto reductase family 1, member A1 activity was examined by multiple linear regression. AKR1C3 Aldo-keto reductase family 1, member C3 Results CBR1 was the most abundant transcript (average relative AKR7A2 Aldo-keto reductase family 7, member A2 expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most AKRs Aldo-keto reductases abundant protein (average relative expression; DS: 38%, non- CBR1 Carbonyl reductase 1 DS: 35%). Positive associations between cardiac CBR1 protein CBR3 Carbonyl reductase 3 levels and daunorubicin reductase activity were found for samples CBRs Carbonyl reductases from donors with- and without- DS. Regression analysis suggests DS Down syndrome that sex, CBR1, AKR1A1, and AKR7A2 protein levels were LOD Limit of detection significant contributors to cardiac daunorubicin reductase activity. LOQ Limit of quantification Electronic supplementary material The online version of this article (doi:10.1007/s11095-013-1267-1) contains supplementary material, which is available to authorized users. : : : * A. Quiñones-Lombraña: D. Ferguson J. L. Kalabus J. G. Blanco ( ) A. Redzematovic J. G. Blanco Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences University at Buffalo, The State University of New York, 470 Kapoor Hall School of Pharmacy and Pharmaceutical Sciences Buffalo, New York 14214-8033, USA The State University of New York at Buffalo e-mail: [email protected] Buffalo, New York, USA R. Hageman Blair Department of Biostatistics School of Public Health and Health Professions The State University of New York at Buffalo Buffalo, New York, USA Quiñones-Lombraña et al. INTRODUCTION goal of this study was to document the extent of interindivid- ual variability in the expression of CBR1, CBR3, AKR1A1, In humans, carbonyl reductases (CBRs) and aldo-keto reduc- AKR1C3 and AKR7A2 in a collection of heart samples from tases (AKRs) play predominant roles during the metabolism of donors with- and without- DS. The expression of CBRs and more than 30 clinically relevant drugs including the antipsy- AKRs was examined by quantitative real time PCR (qRT- chotic agent haloperidol, the opioid receptor antagonist naltrex- PCR) with specific primers, quantitative immunoblotting with one, the antiemetic dolasetron, the anti-inflammatory specific antibodies, and enzyme activity assays using the ketoprofen, and the anticancer anthracyclines doxorubicin anthracycline substrate daunorubicin. We also examined the and daunorubicin (1–3). The use of anthracyclines for the impact of a functional polymorphism in CBR1 (rs9024), chemotherapy of a variety of solid and hematological cancers known to impact CBR1 expression and daunorubicinol syn- is limited by the development of cardiotoxicity in some patients thesis in liver, on cardiac CBR1 gene expression and enzy- (4). For example, a study of children (n =115) who survived matic activity for the substrate daunorubicin (21,24,25). leukemia revealed that 60% of those treated with anthracyclines developed preclinical abnormalities in cardiac structure and function (5). Of note, pediatric cancer patients with Down MATERIALS AND METHODS syndrome (DS, trisomy 21) constitute a population at particu- larly greater risk for anthracycline-related cardiotoxicity, and a Human Heart Samples safe dose of anthracyclines for cancer patients with- DS remains to be defined (6,7). For example, children with- DS represent The Institutional Review Board of the State University of New 15% of pediatric acute myeloid leukemia (AML) cases, and a York at Buffalo approved this research. Heart samples from report from the Children’s Oncology group has documented donors with- (n =9) and without- DS (n =30) were procured clinically symptomatic cardiomyopathy in 17.5% of DS-AML from The National Disease Research Interchange (NDRI, patients treated with an anthracycline-containing regimen (7,8). funded by the National Center for Research Resources), The The complex pathogenesis of anthracycline-related Cooperative Human Tissue Network (CHTN, funded by the cardiotoxicity is mediated by a combination of oxidative stress National Cancer Institute), and the National Institute of Child and metabolic perturbations in myocardial tissue that are in- Health and Human Development (NICHD) Brain and Tissue duced by the C-13 anthracycline alcohol metabolites, whose Bank. The postmortem to tissue recovery interval was ≤10 h. formation is catalyzed by specific CBRs and AKRs (4,9–12). A Samples (2–20 g, myocardium, left ventricle only) were frozen growing cumulus of evidence indicates that two monomeric immediatelyafterrecoveryandstoredinliquidnitrogenuntil CBRs, namely CBR1 and CBR3, together with the members further processing. The main demographics from donors with- of the AKRs superfamily AKR1A1, AKR1C3 and AKR7A2 and without- DS are summarized in Supplementary Material catalyze the synthesis of cardiotoxic C-13 anthracycline alcohol Table I. Down syndrome status (yes/no) and relevant diagnoses metabolites (e.g., daunorubicinol and doxorubicinol) (13–16). In (Supplementary Material Table II) were obtained from anony- addition specific CBRs/AKRs genetic variants may contribute to mous medical histories. Heart samples were processed following the unpredictable pharmacological profile of anthracyclines in standardized procedures to isolate DNA and RNA as described cancer patients (17–19). For example, a recent study from the (24,26). Children’s Oncology group described the impact of functional single nucleotide polymorphisms in CBR1 and CBR3 on the risk Array CGH Analysis of anthracycline-related cardiomyopathy in childhood cancer survivors (20). Thus, interindividual variability in the expression Down syndrome status was confirmed by array comparative of CBRs and AKRs would impact the intracardiac formation of genomic hybridization (aCGH). Briefly, genomic DNA (3.0 μg) cardiotoxic C-13 anthracycline alcohol metabolites, and conse- from test samples and a euploid reference DNA sample were quently the pharmacodynamics of anthracycline drugs. fluorescentlylabeledandhybridizedtohighresolutionAgilent Furthermore, the CBR1 and CBR3 genesarelocatedinthe 244 K aCGH arrays containing +236,000 coding and non- DS critical region of chromosome 21 (21q21-21q22.3). The coding human probes. Changes in DNA copy number were alteredexpressionofCBRs as a result of the gene dosage effect determined by evaluating log2 ratios across whole chromo- may contribute to the increased risk of anthracycline-related somes. aCGH assays were performed at the Genomics core cardiotoxicity in cancer patients with- DS (21). facility, Roswell Park Cancer Institute (Buffalo, NY). In spite of the prominent contributions of CBRs and AKRs towards the pharmacodynamics of anthracycline drugs, re- Quantitative Real-Time PCR ports documenting gene expression levels and protein abun- dance in cardiac tissue are limited to the analysis of individual Cardiac CBR1, CBR3, AKR1A1, AKR1C3,andAKR7A2 samples or pooled tissue samples (13,22,23). Thus, the main mRNA expression was analyzed by qRT-PCR with gene Anthracycline Reductase Expression in Human Hearts specific primers (Table I) following the MIQE guidelines (27). AkR1C3 and AKR7A2, and 40 μg for CBR3) and corre- Briefly, 5 ng of total RNA was reverse transcribed and ampli- sponding recombinant protein standards (Abcam, fied using the one-step QuantiTect SYBR Green RT-PCR kit Cambridge, England) were separated by gel electrophoresis (Qiagen, Venlo, The Netherlands). Target genes and ACTB using NuPAGE Novex 4 - 12% Bis-Tris precast gels, and (reference gene) were amplified in parallel with the following transferred onto nitrocellulose membranes using the iBlot cycling parameters: 50°C for 30 min (reverse transcription), Gel Transfer Device (Invitrogen). Membranes were blocked 95°C for 10 min (Taq DNA polymerase activation), 40 cycles with 5% non-fat milk in 0.2% Tween 20-PBS for 1 h at room of 95°C for 15 s (denaturation), 56°C
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