INTRODUCTION: Against the background of significant progress in anticancer therapy, which makes it possible to improve the quality of life and life expectancy of patients with cancer, anthracycline antibio-tics retain their relevance, both for scientific research and for clinical practice. However, the therapeutic efficacy of anthracyclines is associated with the development of various complications, among which the most common is cardiotoxicity. Our study was dedicated to searching for possible associations between rs4673 and rs28714259 single nucleotide polymorphisms (SNPs) and the risk of cardiotoxicity in breast cancer patients who underwent anthracycline-containing chemotherapy. MATERIALS AND METHODS: The study included 256 patients with a dia-gnosis of breast cancer without dia-gnosed cardiovascular changes who were treated at the National Medical Research Center of Oncology in Rostov-on-Don in 2019-2020. For SNP genotyping, DNA was extracted from blood and high resolution melting analysis was performed. The presence of SNPs was confirmed by Sanger sequencing. RESULTS: The presence of the T-allele rs4673 increased the risk of cardiotoxicity in breast cancer patients 6.49x (95% CI 1.48-28.53; P = 0.002), and the presence of the A-allele rs28714259 increased the risk 3.27x (95% CI 1.23-8.75; P = 0.026). For tests based on genotyping rs4673 and rs28714259 SNPs, the areas under the receiver operating characteristic (ROC) curves were equal to 71.9% and 76.3%, respectively. The two-locus SNP-SNP model turned out to be statistically significant: the training balanced accuracy was 0.77; similarly, the testing balanced accuracy, and the cross-validation consistency was 10/10. CONCLUSION: Our study confirmed the predictive value of genetic tests based on the determination of the rs4673 and rs28714259 SNPs. Genotyping of both SNPs will significantly improve the accuracy of predicting the development of cardiotoxicity against the background of anthracycline-containing therapy and timely identify the risk group of breast cancer patients for whom it is necessary to adjust the therapeutic strategy.

• Klíčová slova
• SNP-SNP interactions, anthracycline-mediated cardiotoxicity– rs4673, breast cancer, rs28714259,
• MeSH
• antracykliny škodlivé účinky   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus MeSH
• kardiotoxicita etiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory prsu farmakoterapie   genetika   MeSH
• NADPH-oxidasy genetika   MeSH
• protinádorová antibiotika škodlivé účinky   MeSH
• riziko MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antracykliny MeSH
• CYBA protein, human MeSH Prohlížeč
• NADPH-oxidasy MeSH
• protinádorová antibiotika MeSH

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.

• MeSH
• antracykliny škodlivé účinky   toxicita   MeSH
• chelátory železa škodlivé účinky   farmakologie   terapeutické užití   MeSH
• kardiotonika * MeSH
• lidé MeSH
• nemoci srdce chemicky indukované   metabolismus   prevence a kontrola   MeSH
• oxidační stres účinky léků   MeSH
• protinádorová antibiotika škodlivé účinky   toxicita   MeSH
• železo fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antracykliny MeSH
• chelátory železa MeSH
• kardiotonika * MeSH
• protinádorová antibiotika MeSH
• železo MeSH

Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of anthracycline antibiotics. During adsorption on a titania dioxide surface, four degradation products of MTX, mitoxantrone dicarboxylic acid, 1,4-dihydroxy-5-((2-((2-hydroxyethyl)amino)ethyl)amino)-8-((2-(methylamino)ethyl)amino)anthracene-9,10-dione, 1,4-dihydroxy-5,8-diiminoanthracene-9,10(5H,8H)-dione and 1,4-dihydroxy-5-imino-8-(methyleneamino)anthracene-9,10(5H,8H)-dione, were identified. In the case of photocatalytic degradation, only one degradation product after 15 min at m/z 472 was identified. This degradation product corresponded to mitoxantrone dicarboxylic acid, and complete mineralization was attained in one hour. Destructive adsorbent manganese(IV) oxide, MnO2, was used only for the destructive adsorption of MTX. Destructive adsorption occurred only for one degradation product, mitoxantrone dicarboxylic acid, against anatase TiO2.

• MeSH
• adsorpce MeSH
• antracykliny chemie   MeSH
• katalýza MeSH
• mitoxantron chemie   MeSH
• nanočástice chemie   MeSH
• oxidy chemie   MeSH
• sloučeniny manganu chemie   MeSH
• titan chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• manganese dioxide MeSH Prohlížeč
• mitoxantron MeSH
• oxidy MeSH
• sloučeniny manganu MeSH
• titan MeSH
• titanium dioxide MeSH Prohlížeč

The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects.

• Klíčová slova
• Aldo-keto reductases, Anthracycline resistance, Cardiotoxicity, Daunorubicin, Enzyme inhibition, Short-chain dehydrogenases/reductases,
• MeSH
• anthrachinony farmakologie   MeSH
• chemorezistence účinky léků   MeSH
• daunomycin farmakologie   MeSH
• emodin farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oxidoreduktasy antagonisté a inhibitory   metabolismus   MeSH
• protinádorová antibiotika farmakologie   MeSH
• simulace molekulového dockingu MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2,6-dihydroxyanthraquinone MeSH Prohlížeč
• anthrachinony MeSH
• daunomycin MeSH
• emodin MeSH
• inhibitory proteinkinas MeSH
• oxidoreduktasy MeSH
• protinádorová antibiotika MeSH

AIM: Monitoring of anthracycline-induced cardiotoxicity with electrocardiography (ECG) and comparing ECG changes with findings on echocardiography (ECHO). METHODS: A total of 26 adult acute leukemia patients (mean age 46.2 -/+ 12.4 years, 15 males) treated with 2-6 cycles of anthracycline-based chemotherapy (CT) were studied. Cardiac evaluation was performed at the baseline (before CT), after first CT, after last CT (cumulative anthracycline dose 464.3 -/+ 117.5 mg/m2) and circa 6 months after CT. Time ECG parameters, QRS voltage, presence of repolarization changes, arrhythmias and other abnormalities were evaluated. RESULTS: During treatment and follow-up, we found a statistical significant QTc interval prolongation - 414.7 -/+ 16.0 ms (before CT), 419.6 -/+ 21.6 ms (after first CT), 428.0 -/+ 16.2 ms (after last CT) and 430.1 -/+ 18.4 ms (6 months after CT). Significant QTc interval prolongation (> 450 ms) occurred in 3 patients after first CT, in 4 patients after last CT and in 5 patients within 6 months after CT. Significant total QRS voltage lowering in the limb leads (> 1.0 mV versus before CT) occurred in 3 patients after first CT, in 5 patients after last CT and in 6 patients within 6 months after CT. We found a statistically significant correlation between decreased QRS voltage, QTc interval prolongation and left ventricular (LV) dysfunction on ECHO. Repolarization changes associated with oncology treatment were present in 9 patients within 6 months after CT. CONCLUSION: Anthracycline treatment is associated with changes in electrical activity of the myocardium. Prolonged QTc interval represents a risk for development of malignant ventricular arrhythmias. Decreased QRS voltage and prolonged QTc interval after anthracycline treatment could correlate with LV dysfunction on ECHO. Further studies will be needed to prove whether these ECG changes could serve as an accessible and non-invasive screening method indicating LV dysfunction after anthracycline treatment.

• MeSH
• antracykliny škodlivé účinky   MeSH
• dospělí MeSH
• echokardiografie MeSH
• elektrokardiografie * MeSH
• leukemie farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• protinádorové látky škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• srdce účinky léků   MeSH
• srdeční arytmie chemicky indukované   diagnóza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antracykliny MeSH
• protinádorové látky MeSH

BACKGROUND: Cardiotoxicity is a well-known and potentially serious complication of anticancer therapy. Anthracycline-based chemotherapy represents the greatest risk. Early detection of cardiotoxicity is crucial for applying preventive and supportive therapeutic strategies. METHODS AND RESULTS: Various methods have been recommended for monitoring of cardiotoxicity. In our conditions, echocardiography and electrocardiography are routinely used. However, this approach shows low sensitivity for the early prediction of cardiomyopathy when the possibilities of appropriate management could still improve the patient's outcome. Recently, biomarkers of cardiac injury have been investigated in the assessment of chemotherapy-induced cardiotoxicity. Cardiospecific biomarkers, such as cardiac troponins, show high diagnostic efficacy in the early subclinical phase of the disease before the clinical onset of cardiomyopathy. Increase in their concentrations correlates with disease severity. As for natriuretic peptides, some studies, including ours, have shown promising results. Definitive evidence of their diagnostic and prognostic role in this context is still lacking and natriuretic peptides have not been routinely used for monitoring of cardiotoxicity in clinical practice. Other perspective biomarkers of cardiotoxicity in oncology are under study, especially heart-type fatty acid-binding protein (H-FABP) and glycogen phosphorylase BB (GPBB). Our studies using GPBB have provided encouraging results. However, the available data are limited and their practical use in this context cannot be recommended until their clinical efficacy is clearly defined. CONCLUSIONS: This review covers the current status of biomarkers for the early detection of anthracycline-induced cardiotoxicity. The authors present in brief, their own experience with multiple biomarkers in the detection of cardiotoxicity.

• MeSH
• antracykliny škodlivé účinky   MeSH
• biologické markery analýza   MeSH
• kardiotoxicita diagnóza   etiologie   MeSH
• lidé MeSH
• protinádorová antibiotika škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antracykliny MeSH
• biologické markery MeSH
• protinádorová antibiotika MeSH

Chronic anthracycline cardiotoxicity is a feared complication of cancer chemotherapy. However, despite several decades of primarily hypothesis-driven research, the molecular basis of this phenomenon remains poorly understood. The aim of this study was to obtain integrative molecular insights into chronic anthracycline cardiotoxicity and the resulting heart failure. Cardiotoxicity was induced in rabbits (daunorubicin 3mg/kg, weekly, 10weeks) and changes in the left ventricular proteome were analyzed by 2D-DIGE. The protein spots with significant changes (p<0.01, >1.5-fold) were identified using MALDI-TOF/TOF. Key data were corroborated by immunohistochemistry, qRT-PCR and enzyme activity determination and compared with functional, morphological and biochemical data. The most important alterations were found in mitochondria - especially in proteins crucial for oxidative phosphorylation, energy channeling, antioxidant defense and mitochondrial stress. Furthermore, the intermediate filament desmin, which interacts with mitochondria, was determined to be distinctly up-regulated and disorganized in its expression pattern. Interestingly, the latter changes reflected the intensity of toxic damage in whole hearts as well as in individual cells. In addition, a marked drop in myosin light chain isoforms, activation of proteolytic machinery (including the proteasome system), increased abundance of chaperones and proteins involved in chaperone-mediated autophagy, membrane repair as well as apoptosis were found. In addition, dramatic changes in proteins of basement membrane and extracellular matrix were documented. In conclusion, for the first time, the complex proteomic signature of chronic anthracycline cardiotoxicity was revealed which enhances our understanding of the basis for this phenomenon and it may enhance efforts in targeting its reduction.

• MeSH
• 2D gelová elektroforéza MeSH
• antracykliny toxicita   MeSH
• daunomycin toxicita   MeSH
• echokardiografie MeSH
• extracelulární matrix účinky léků   metabolismus   MeSH
• imunohistochemie MeSH
• králíci MeSH
• malondialdehyd metabolismus   MeSH
• mitochondriální proteiny metabolismus   MeSH
• myokard metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proteomika MeSH
• srdeční komory účinky léků   metabolismus   MeSH
• srdeční selhání chemicky indukované   metabolismus   MeSH
• troponin I metabolismus   MeSH
• vimentin metabolismus   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• malondialdehyd MeSH
• mitochondriální proteiny MeSH
• troponin I MeSH
• vimentin MeSH

AIM: Assessment of acute and chronic cardiotoxicity of anthracyclines in patients treated for acute leukemia (AL) with biochemical markers - "N-terminal pro brain natriuretic peptide" (NT-proBNP), cardiac troponin T (cTnT), creatine kinase MB (CK-MB mass), and echocardiography. METHODS: Twenty-six adult AL patients (mean age 46.2 +/- 12.4 years, 15 males) treated with 2-6 cycles of chemotherapy (CT) containing anthracyclines in the total cumulative dose of 464.3 +/- 117.5 mg/m2 were studied. Cardiac evaluation was performed at baseline, after first and last CT with anthracyclines and 6 months after CT. RESULTS: Mean baseline NT-proBNP concentration was 117.7 +/- 46.4 ng/L (slightly elevated in 3 patients). After first and last CT, NT-proBNP elevations to 299.7 +/- 176.2 ng/L and 287.1 +/- 147.4 ng/L were observed, respectively. Six months after CT, mean NT-proBNP concentration was 362.5 +/- 304.9 ng/L (elevated in 16 patients). Changes in NT-proBNP were significant in comparison with the baseline values (p < 0.001). Six months after CT, two patients with marked NT-proBNP elevations during CT developed treatment-related cardiomyopathy with symptoms of heart failure. NT-proBNP correlated with systolic and diastolic LV dysfunction on echocardiography (r = 0.514; p < 0.01) and (r = 0.587; p < 0.01). CTnT concentrations were negative (bellow 0.01 microg/L) during CT in all patients. Six months after CT, delayed cTnT positivity occurred in 3 patients. CK-MB mass remained within the reference range in all patients. CONCLUSION: Our study shows that anthracycline treatment is associated with acute and chronic neurohumoral activation of cardiac dysfunction that is manifested by a significant increase in NT-proBNP. It seems that NT-proBNP could be useful in the early detection of anthracycline cardiotoxicity. CTnT negativity during anthracycline treatment suggests that anthracyclines, even in higher cumulative doses, do not cause detectable acute injury to cardiomyocyte structure. Further studies using more sensitive markers of cardiac damage will be needed in this context.

• MeSH
• akutní nemoc MeSH
• antracykliny škodlivé účinky   MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• echokardiografie MeSH
• kreatinkinasa, forma MB krev   MeSH
• leukemie farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• natriuretický peptid typu B krev   MeSH
• nemoci srdce krev   chemicky indukované   MeSH
• peptidové fragmenty krev   MeSH
• senzitivita a specificita MeSH
• troponin T krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• biologické markery MeSH
• kreatinkinasa, forma MB MeSH
• natriuretický peptid typu B MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
• troponin T MeSH

Anthracycline cardiotoxicity ranks among the most severe complications of cancer chemotherapy. Although its pathogenesis is only incompletely understood, "reactive oxygen species (ROS) and iron" hypothesis has gained the widest acceptance. Besides dexrazoxane, novel oral iron chelator deferiprone has been recently reported to afford significant cardioprotection in both in vitro and ex vivo conditions. Therefore, the aim of this study was to assess whether deferiprone 1) has any effect on the anticancer action of daunorubicin and 2) whether it can overcome or significantly reduce the chronic anthracycline cardiotoxicity in the in vivo rabbit model (daunorubicin, 3 mg/kg i.v., weekly for 10 weeks). First, using the leukemic cell line, deferiprone (1-300 microM) was shown not to blunt the antiproliferative effect of daunorubicin. Instead, in clinically relevant concentrations (>10 microM), deferiprone augmented the antiproliferative action of daunorubicin. However, deferiprone (10 or 50 mg/kg administered p.o. before each daunorubicin dose) failed to afford significant protection against daunorubicin-induced mortality, left ventricular lipoperoxidation, cardiac dysfunction, and morphological cardiac deteriorations, as well as an increase in plasma cardiac troponin T. Hence, this first in vivo study changes the current view on deferiprone as a potential cardioprotectant against anthracycline cardiotoxicity. In addition, these results, together with our previous findings, further suggest that the role of iron and its chelation in anthracycline cardiotoxicity is not as trivial as originally believed and/or other mechanisms unrelated to iron-catalyzed ROS production are involved.

• MeSH
• antracykliny aplikace a dávkování   antagonisté a inhibitory   toxicita   MeSH
• daunomycin antagonisté a inhibitory   MeSH
• deferipron MeSH
• HL-60 buňky MeSH
• kardiotonika terapeutické užití   toxicita   MeSH
• králíci MeSH
• lidé MeSH
• nemoci srdce chemicky indukované   mortalita   patologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky terapeutické užití   toxicita   MeSH
• pyridony terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• deferipron MeSH
• kardiotonika MeSH
• protinádorové látky MeSH
• pyridony MeSH

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this "ROS and iron" hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized "ROS and iron" hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.

• MeSH
• antracykliny škodlivé účinky   farmakologie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nemoci srdce chemicky indukované   patofyziologie   MeSH
• oxidační stres účinky léků   MeSH
• protinádorová antibiotika škodlivé účinky   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rizikové faktory MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antracykliny MeSH
• protinádorová antibiotika MeSH
• reaktivní formy kyslíku MeSH
• železo MeSH