Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent ANT-induced cardiac damage and provide long-lasting cardioprotection. The present study aimed to examine the cardioprotective effects of perindopril on chronic ANT cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane (DEX) with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (DAU; 3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic DAU treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of DAU-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T (cTnT) levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure (HF)-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented HF-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for DEX in the same model. Hence, in the present study, perindopril provided only temporary control of ANT cardiotoxicity development, which may be associated with the lack of effects on ANT-induced and topoisomerase II β (TOP2B)-dependent DNA damage responses in the heart.

• MeSH
• antibiotika antitumorózní MeSH
• daunomycin škodlivé účinky   MeSH
• inhibitory ACE terapeutické užití   MeSH
• kardiotoxicita farmakoterapie   prevence a kontrola   MeSH
• králíci MeSH
• nemoci srdce chemicky indukované   prevence a kontrola   MeSH
• perindopril terapeutické užití   MeSH
• srdeční selhání farmakoterapie   mortalita   MeSH
• troponin T krev   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. METHODS: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). RESULTS: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. CONCLUSIONS: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.

• MeSH
• antibiotika antitumorózní škodlivé účinky   farmakologie   MeSH
• antracykliny škodlivé účinky   farmakologie   MeSH
• daunomycin metabolismus   farmakologie   MeSH
• dexrazoxan škodlivé účinky   farmakologie   MeSH
• DNA-topoisomerasy typu II škodlivé účinky   metabolismus   MeSH
• inhibitory topoisomerasy II metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kardiotoxicita farmakoterapie   metabolismus   prevence a kontrola   MeSH
• lidé MeSH
• nemoci srdce farmakoterapie   MeSH
• oxidační stres účinky léků   MeSH
• srdeční selhání farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.

• MeSH
• daunomycin toxicita   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• inhibitory topoisomerasy II chemická syntéza   metabolismus   terapeutické užití   MeSH
• kardiomyocyty účinky léků   MeSH
• kardiotonika chemická syntéza   metabolismus   terapeutické užití   MeSH
• kardiotoxicita farmakoterapie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• novorozená zvířata MeSH
• piperaziny chemická syntéza   metabolismus   terapeutické užití   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• Saccharomyces cerevisiae - proteiny metabolismus   MeSH
• Saccharomyces cerevisiae chemie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

• MeSH
• antracykliny škodlivé účinky   MeSH
• dexrazoxan chemie   farmakologie   MeSH
• diketopiperaziny chemie   farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• inhibitory topoisomerasy II chemie   farmakologie   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kardiotonika chemie   farmakologie   MeSH
• kardiotoxicita farmakoterapie   metabolismus   MeSH
• králíci MeSH
• piperazin chemie   farmakologie   MeSH
• prekurzory léčiv chemie   farmakologie   MeSH
• razoxan chemie   farmakologie   MeSH
• voda chemie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase IIβ (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT: This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIβ as an upstream druggable target for effective and clinically translatable cardioprotection.

• MeSH
• antracykliny škodlivé účinky   MeSH
• dexrazoxan farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kardiomyopatie farmakoterapie   metabolismus   MeSH
• kardiotoxicita farmakoterapie   MeSH
• králíci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely u zvířat MeSH
• myokard metabolismus   MeSH
• nádorové buněčné linie MeSH
• ochranné látky farmakologie   MeSH
• potkani Wistar MeSH
• srdce účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Novel dexrazoxane derivative JR-311 was prepared to investigate structure-activity relationships and mechanism(s) of protection against anthracycline cardiotoxicity. Its cardioprotective, antiproliferative, iron (Fe) chelation and inhibitory and/or depletory activities on topoisomerase IIbeta (TOP2B) were examined and compared with dexrazoxane. While in standard assay, JR-311 failed in both cardioprotection and depletion of TOP2B, its repeated administration to cell culture media led to depletion of TOP2B and significant protection of isolated rat neonatal ventricular cardiomyocytes from daunorubicin-induced damage. This effect was explained by a focused analytical investigation that revealed rapid JR-311 decomposition, resulting in negligible intracellular concentrations of the parent compound but high exposure of cells to the decomposition products, including Fe-chelating JR-H2. Although chemical instability is an obstacle for the development of JR-311, this study identified a novel dexrazoxane analogue with preserved pharmacodynamic properties, contributed to the investigation of structure-activity relationships and suggested that the cardioprotection of bis-dioxopiperazines is likely attributed to TOP2B activity of the parent compound rather than Fe chelation of their hydrolytic metabolites/degradation products. Moreover, this study highlights the importance of early stability testing during future development of novel dexrazoxane analogues.

• MeSH
• antracykliny toxicita   MeSH
• chelátory železa farmakologie   MeSH
• daunomycin toxicita   MeSH
• dexrazoxan analogy a deriváty   farmakologie   MeSH
• diketopiperaziny farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• kardiomyocyty účinky léků   MeSH
• kardiotonika farmakologie   MeSH
• kardiotoxicita farmakoterapie   etiologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• akutní poškození ledvin chemicky indukované   farmakoterapie   MeSH
• anemie chemicky indukované   farmakoterapie   MeSH
• antiemetika terapeutické užití   MeSH
• antitumorózní látky * škodlivé účinky   terapeutické užití   MeSH
• chemoprofylaxe MeSH
• febrilní neutropenie vyvolaná chemoterapií farmakoterapie   prevence a kontrola   MeSH
• kardiotoxicita etiologie   farmakoterapie   prevence a kontrola   MeSH
• lidé MeSH
• nežádoucí účinky léčiv epidemiologie   etiologie   farmakoterapie   MeSH
• oportunní infekce chemicky indukované   farmakoterapie   MeSH
• průjem chemicky indukované   farmakoterapie   MeSH
• radioterapie * škodlivé účinky   MeSH
• trombocytopenie chemicky indukované   farmakoterapie   MeSH
• zvracení etiologie   farmakoterapie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• antiflogistika nesteroidní * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• bolest * farmakoterapie   komplikace   MeSH
• gastrointestinální krvácení etiologie   farmakoterapie   terapie   MeSH
• gastrointestinální nemoci komplikace   prevence a kontrola   MeSH
• játra účinky léků   MeSH
• kardiotoxicita farmakoterapie   komplikace   MeSH
• kardiovaskulární nemoci komplikace   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• nežádoucí účinky léčiv farmakoterapie   komplikace   MeSH
• paracetamol * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• renální insuficience komplikace   MeSH
• statistika jako téma MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH

Catecholamines are endogenous amines that participate in the maintenance of cardiovascular system homeostasis. However, excessive release or exogenous administration of catecholamines is cardiotoxic. The synthetic catecholamine, isoprenaline (isoproterenol, ISO), with non-selective β-agonistic activity has been used as a viable model of acute myocardial toxicity for many years. Since the pathophysiology of ISO-cardiotoxicity is complex, the aim of this study was to elucidate the effect of oral quercetin pretreatment on myocardial ISO toxicity. Wistar-Han rats were randomly divided into four groups: solvent or quercetin administered orally by gavage in a dose of 10 mg kg(-1) daily for 7 days were followed by s.c. water for injection or ISO in a dose of 100 mg kg(-1). Haemodynamic, ECG and biochemical parameters were measured; effects on blood vessels and myocardial histology were assessed, and accompanying pharmacokinetic analysis was performed. Quercetin was unable to protect the cardiovascular system against acute ISO cardiotoxicity (stroke volume decrease, cardiac troponin T release, QRS-T junction elevation and histological impairment). The sole positive effect of quercetin on catecholamine-induced cardiotoxicity was the normalization of increased left ventricular end-diastolic pressure caused by ISO. Quercetin did not reverse the increased responsiveness of rat aorta to vasoconstriction in ISO-treated animals, but it decreased the same parameter in the control animals. Accompanying pharmacokinetic analysis showed absorption of quercetin and its metabolite 3-hydroxyphenylacetic acid formed by bacterial microflora. In conclusion, a daily oral dose of 10 mg kg(-1) of quercetin for 7 days did not ameliorate acute ISO-cardiovascular toxicity in rats despite minor positive cardiovascular effects.

• MeSH
• aorta thoracica účinky léků   fyziologie   MeSH
• aplikace orální MeSH
• hemodynamika MeSH
• isoprenalin MeSH
• kardiotoxicita krev   farmakoterapie   patologie   patofyziologie   MeSH
• krysa rodu rattus MeSH
• myokard patologie   MeSH
• quercetin krev   farmakokinetika   terapeutické užití   MeSH
• troponin T krev   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• anestetika lokální škodlivé účinky   MeSH
• antikonvulziva aplikace a dávkování   MeSH
• kardiotoxicita farmakoterapie   patofyziologie   prevence a kontrola   MeSH
• lidé MeSH
• neurotoxické syndromy etiologie   farmakoterapie   MeSH
• nežádoucí účinky léčiv MeSH
• porodnická anestezie * metody   škodlivé účinky   MeSH
• těhotenství MeSH
• tukové emulze intravenózní aplikace a dávkování   MeSH
• způsoby aplikace léků MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH