Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes. We examined the putative topoisomerase IIβ selective agent XK469 as a potential cardioprotective and designed several new analogs. In our experiments, XK469 inhibited both topoisomerase isoforms (α and β) and did not induce topoisomerase II covalent complexes in isolated cardiomyocytes and HL-60, but induced proteasomal degradation of topoisomerase II in these cell types. The cardioprotective potential of XK469 was studied on rat neonatal cardiomyocytes, where dexrazoxane (ICRF-187), the only clinically approved cardioprotective, was effective. Initially, XK469 prevented daunorubicin-induced toxicity and p53 phosphorylation in cardiomyocytes. However, it only partially prevented the phosphorylation of H2AX and did not affect DNA damage measured by Comet Assay. It also did not compromise the daunorubicin antiproliferative effect in HL-60 leukemic cells. When administered to rabbits to evaluate its cardioprotective potential in vivo, XK469 failed to prevent the daunorubicin-induced cardiac toxicity in either acute or chronic settings. In the following in vitro analysis, we found that prolonged and continuous exposure of rat neonatal cardiomyocytes to XK469 led to significant toxicity. In conclusion, this study provides important evidence on the effects of XK469 and its combination with daunorubicin in clinically relevant doses in cardiomyocytes. Despite its promising characteristics, long-term treatments and in vivo experiments have not confirmed its cardioprotective potential.

• MeSH
• antibiotika antitumorózní toxicita   MeSH
• antracykliny * toxicita   terapeutické užití   MeSH
• chinoxaliny * MeSH
• daunomycin toxicita   terapeutické užití   MeSH
• DNA-topoisomerasy typu II metabolismus   terapeutické užití   MeSH
• doxorubicin toxicita   MeSH
• inhibitory topoisomerasy II * toxicita   terapeutické užití   MeSH
• kardiotoxicita MeSH
• králíci MeSH
• krysa rodu rattus MeSH
• poškození DNA MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Doxorubicin (DOX) is a cytostatic agent belonging to anthracycline group. Important role in mechanism associated with negative effects of DOX plays an oxidative stress. Heat shock proteins (HSPs) are part of mechanisms initiated in response to stressful stimuli and play an important role in cellular responses to oxidative stress through interaction with components of redox signaling. The present work was aimed to study the role of HSPs and autophagy in mechanisms underlying effects of sulforaphane (SFN), a potential activator of Nrf-2, on doxorubicin-induced toxicity in human kidney HEK293 cells. We investigated effects of SFN and DOX on proteins associated with regulation of heat shock response, redox signaling, and autophagy. Results show that SFN significantly reduced cytotoxic effects of DOX. The positive effects of SFN on DOX-induced changes were associated with up-regulation of Nrf-2 and HSP60 protein levels. In the case of another heat shock protein HSP40, SFN increased its levels when was administered alone but not in conditions when cells were exposed to the effects of DOX. Sulforaphane also reversed negative effects of DOX on activities of superoxide dismutases (SODs) and up-regulation of autophagy markers (LC3A/B-II, Atg5, and Atg12). In conclusion, the changes observed in HSP60 are of particular importance in terms of protecting cells from the effects of DOX. Finding that under conditions where SFN reduced cytotoxic effects of DOX were significantly increased protein levels of both Nrf-2 and HSP60 point to the role of HSP60 in mechanisms of redox signaling underlying effects of SFN on DOX-induced toxicity in HEK293 cells. Moreover, data confirmed an important role of autophagy in effects of SFN on DOX-induced toxicity.

• MeSH
• apoptóza MeSH
• autofagie MeSH
• doxorubicin * toxicita   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• oxidační stres MeSH
• proteiny tepelného šoku * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Karcinom prsu představuje heterogenní onemocnění. I přes rozšíření nových terapeutických možností pro jednotlivé podtypy karcinomu chemoterapie stále zaujímá důležité místo v adjuvantní léčbě i v léčbě metastatického onemocnění. Cílem léčby metastatického onemocnění je prodloužení života a udržení jeho kvality. Pořadí léčebných modalit a přípravků se stanovuje pro každou pacientku individuálně. Antracykliny mají významné postavení z hlediska účinnosti léčby. V managementu metastatického onemocnění je problémem jejich kumulativní dávka, při jejímž překročení se výrazně zvyšuje kardiotoxicita. Snížení dávky při současném zachování účinnosti lze dosáhnout využitím lipozomálních forem léků.

Breast cancer is a heterogeneous disease. Despite the expansion of new therapeutic options for individual subtypes, chemotherapy still plays an important role in adjuvant treatment as well as in the treatment of metastatic disease. The goal of treating metastatic disease is to prolong life and maintain its quality. The order of treatment modalities and preparations is individual for each patient. Anthracyclines have an important place for their efficiency. A problem in the management of metastatic disease is their cumulative dose, above which cardiotoxicity increases significantly. Its reduction and at the same time maintaining efficiency can be achieved by using liposomal forms.

• Klíčová slova
• lipozomální doxorubicin,
• MeSH
• doxorubicin * aplikace a dávkování   terapeutické užití   toxicita   MeSH
• karcinom farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• liposomy terapeutické užití   MeSH
• metastázy nádorů farmakoterapie   MeSH
• nádory prsu farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Doxorubicin's (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic for the transition stage between the compensated and decompensated phases of HF. In conclusion, we suggest that DOX-induced HF in TGR is a suitable model to study the pathophysiological aspects of chemotherapy-induced HF and to evaluate novel therapeutic strategies to combat this form of HF, which are urgently needed.

• MeSH
• antitumorózní látky toxicita   MeSH
• doxorubicin toxicita   MeSH
• kardiotoxicita MeSH
• krevní tlak * MeSH
• krysa rodu rattus MeSH
• potkani Sprague-Dawley MeSH
• renin-angiotensin systém * MeSH
• renin genetika   MeSH
• srdeční selhání etiologie   metabolismus   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Modern diagnostic strategies for early recognition of cancer therapeutics-related cardiac dysfunction involve cardiac troponins measurement. Still, the role of other markers of cardiotoxicity is still unclear. The present study was designed to investigate dynamics of response of human cardiomyocytes derived from induced pluripotent stem cells (hiPCS-CMs) to doxorubicin with the special emphasis on their morphological changes in relation to expression and organization of troponins. The hiPCS-CMs were treated with doxorubicin concentrations (1 and 0.3 µM) for 48 h and followed for next up to 6 days. Exposure of hiPCS-CMs to 1 µM doxorubicininduced suppression of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) gene expression. Conversely, lower 0.3 µM doxorubicin concentration produced no significant changes in the expression of aforementioned genes. However, the intracellular topography, arrangement, and abundance of cardiac troponin proteins markedly changed after both doxorubicin concentrations. In particular, at 48 h of treatment, both cTnT and cTnI bundles started to reorganize, with some of them forming compacted shapes extending outwards and protruding outside the cells. At later intervals (72 h and onwards), the whole troponin network collapsed and became highly disorganized following, to some degree, overall changes in the cellular shape. Moreover, membrane permeability of cardiomyocytes was increased, and intracellular mitochondrial network rearranged and hypofunctional. Together, our results demonstrate complex effects of clinically relevant doxorubicin concentrations on hiPCS-CM cells including changes in cTnT and cTnI, but also in other cellular compartments contributing to the overall cytotoxicity of this class of cytostatics.

• MeSH
• antitumorózní látky farmakologie   toxicita   MeSH
• buněčné linie MeSH
• doxorubicin farmakologie   toxicita   MeSH
• indukované pluripotentní kmenové buňky cytologie   účinky léků   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kardiotoxicita MeSH
• lidé MeSH
• troponin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cardiotoxicity is a serious adverse reaction to cancer chemotherapy and may lead to critical heart damage. Imatinib mesylate (IMB), a selective tyrosine kinase inhibitor, is sometimes accompanied by severe cardiovascular complications. To minimize risk, early biomarkers of such complications are of utmost importance. At the present time, microRNAs (miRNAs) are intensively studied as potential biomarkers of many pathological processes. Many miRNAs appear to be specific in some tissues, including the heart. In the present study we have explored the potential of specific miRNAs to be early markers of IMB-induced cardiotoxicity. Doxorubicin (DOX), an anthracycline with well-known cardiotoxicity, was used for comparison. NMRI mice were treated with IMB or DOX for nine days in doses corresponding to the highest recommended doses in oncological patients, following which plasmatic levels of miRNAs were analyzed in miRNA microarrays and selected cardio-specific miRNAs were quantified using qPCR. The plasmatic level of miR-1a, miR-133a, miR-133b, miR-339, miR-7058, miR-6236 and miR-6240 were the most different between the IMB-treated and control mice. Interestingly, most of the miRNAs affected by DOX were also affected by IMB showing the same trends. Concerning selected microRNAs in the hearts of individual mice, only miR-34a was significantly increased after DOX treatment, and only miR-205 was significantly decreased after IMB and DOX treatment. However, no changes in any miRNA expression correlated with the level of troponin T, a classical marker of heart injury.

• MeSH
• doxorubicin toxicita   MeSH
• imatinib mesylát farmakologie   MeSH
• mikro RNA krev   genetika   metabolismus   MeSH
• myši MeSH
• regulace genové exprese účinky léků   MeSH
• srdce účinky léků   MeSH
• transkriptom účinky léků   MeSH
• troponin T krev   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cíl: Cílem této práce bylo vyvinout nanoléčivo založené na specifickém transportu pomocí oligonukleotidové próby (komplementární k BRCA1 genové mutaci) s předpokládaným účinkem cytostatika bez výrazných toxických efektů k nenádorovým buňkám. Použitým cytostatikem bylo antracyklinové antibiotikum doxorubicin. Přes svou terapeutickou účinnost však vykazuje vysokou kardiotoxicitu. Možnost, jak zvýšit terapeutické okno, představují nanotransportéry. Metodika: Doxorubicin a oligonukleotidová próba byly navázány k fullerenům. Doba modifikace nanotransportérů byla 24 h. Nanotransportér byl následně charakterizován pomocí biofyzikálních technik (SEM, dynamického rozptylu světla, spektrální a elektrochemické metody). Pomocí elektrochemické a fluorescenční analýzy byl vzniklý komplex nanotransportéru potvrzen. Výsledky: Doxorubicin se záporně nabitým povrchem interaguje s kladně nabitými fullereny elektrostatickou interakcí a tato interakce byla potvrzena na základě elektronové mikroskopie (SEM), elektrochemicky (změna potenciálu byla 35 mV) a měřením dynamického rozptylu světla (změna ζ-potenciálu byla 22 mV). Ke komplexu byla amidovou vazbou připojena oligonukleotidová proba, která je komplementární k mutované sekvenci BRCA genu. Pokles fluorescenčního signálu nanokonstruktu o 80 % indikoval navázání oligonukleotidu. Pro prokázání funkčnosti byla navržena magnetická zlatá nanočástice modifikovaná komplementární sekvencí k testovanému nanotransportéru. Závěr: Předpokládáme, že navržený nanokonstrukt bude možné využít pro DNA cílené směřování protinádorového léčiva k buňkám s mutací v genu BRCA. Nanotransportér má tyto základní vlastnosti: a) fulleren vykazuje vysokou afinitu k buňce a proniká cytoplazmatickou membránou; b) doxorubicin se uvolní do cytoplazmy v nádorových buňkách díky nízkému pH; c) celý konstrukt je směřován cíleně na mutovanou sekvenci genu BRCA; d) zlatá nanočástice zesiluje cytotoxický efekt

Objective: Main goal of this project was to develop a nanotransporter based on a targeted delivery using oligonucleotide probe, which is complementary to a mutated BRCA1 gene sequence with the expected effect of a cytostatic without significant toxic effects. The mentioned cytostatic is often used doxorubicin. Despite its therapeutic efficacy, however, it exhibits high cardiotoxicity. Nanotransporters represent the possibility of increasing the therapeutic window. Methods: Doxorubicin and oligonucleotide probe were bound to fullerenes. The modification time was 24 hours. The nanotransporter was subsequently characterized by biophysical techniques (SEM, dynamic light scattering, spectral and electrochemical methods.) Using the electrochemical and fluorescence analysis the formation of nanotransporter was confirmed. Results: Doxorubicin with a negatively charged surface interacts with positively charged fullerenes by electrostatic interaction and this interaction was confirmed by on the basis of electron microscopy (SEM), electrochemically (change of potential was 35 mV) and by measurement of dynamic light scattering (change of ζ-potential was 22 mV). Oligonucleotide probe, which is complementary to the BRCA mutated gene sequence, was bound to the complex by an amide bond. The drop of the fluorescence signal by 80% indicated binding of the oligonucleotide. To demonstrate the functionality, a magnetic gold nanoparticle, modified by the complementary sequence to the tested nanotransporter, was developed. Conclusion: We assume, that the proposed nanotransporter will be used for DNA targeted delivery of the antitumor drug to the cells with BRCA mutated genes. The nanotransporter has these basic characteristics: a) fullerene has a high affinity to the cell and penetrates the cell membrane; b) doxorubicin is released into cytoplasm in tumour cells due to low pH; c) the entire construct is targeted to the BRCA mutated gene sequence; d) the gold nanoparticle enhances the cytotoxic effect.

• MeSH
• antibiotika antitumorózní MeSH
• doxorubicin aplikace a dávkování   terapeutické užití   toxicita   MeSH
• fullereny terapeutické užití   MeSH
• geny BRCA1 MeSH
• geny BRCA2 MeSH
• kovové nanočástice využití   MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádory prsu * terapie   MeSH
• nanomedicína * MeSH
• oligonukleotidy terapeutické užití   MeSH
• pilotní projekty MeSH
• systémy cílené aplikace léků MeSH
• zlato terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

• MeSH
• akutní nemoc MeSH
• antitumorózní látky toxicita   MeSH
• doxorubicin toxicita   MeSH
• fullereny farmakologie   MeSH
• játra účinky léků   patologie   MeSH
• krysa rodu rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• lékové postižení jater farmakoterapie   MeSH
• modely nemocí na zvířatech MeSH
• nanočástice chemie   MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani Wistar MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (Mw ~27kDa, Rh ~4nm) and non-degradable star (Mw ~250kDa, Rh ~13nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85mgDOX/kg) and lower for the star conjugate (22.5mgDOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased Rh that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments.

• MeSH
• akrylamidy chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• antibiotika antitumorózní * chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• dendrimery chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• doxorubicin chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• játra účinky léků   patologie   MeSH
• kostní dřeň účinky léků   patologie   MeSH
• maximální tolerovaná dávka MeSH
• molekulová hmotnost MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory krev   farmakoterapie   metabolismus   MeSH
• nosiče léků * chemie   farmakokinetika   terapeutické užití   toxicita   MeSH
• slezina účinky léků   patologie   MeSH
• střeva metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.

• MeSH
• antibiotika antitumorózní toxicita   MeSH
• antracykliny toxicita   MeSH
• chronická nemoc MeSH
• daunomycin toxicita   MeSH
• donory oxidu dusnatého farmakologie   MeSH
• doxorubicin toxicita   MeSH
• kardiotonika farmakologie   MeSH
• kardiotoxicita MeSH
• králíci MeSH
• molsidomin farmakologie   MeSH
• nádorové buněčné linie MeSH
• nemoci srdce chemicky indukované   prevence a kontrola   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• remodelace komor účinky léků   MeSH
• srdeční selhání prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH