Labile redox-active iron ions have been implicated in various neurodegenerative disorders, including the Parkinson's disease (PD). Iron chelation has been successfully used in clinical practice to manage iron overload in diseases such as thalassemia major; however, the use of conventional iron chelators in pathological states without systemic iron overload remains at the preclinical investigative level and is complicated by the risk of adverse outcomes due to systemic iron depletion. In this study, we examined three clinically-used chelators, namely, desferrioxamine, deferiprone and deferasirox and compared them with experimental agent salicylaldehyde isonicotinoyl hydrazone (SIH) and its boronate-masked prochelator BSIH for protection of differentiated PC12 cells against the toxicity of catecholamines 6-hydroxydopamine and dopamine and their oxidation products. All the assayed chelating agents were able to significantly reduce the catecholamine toxicity in a dose-dependent manner. Whereas hydrophilic chelator desferrioxamine exerted protection only at high and clinically unachievable concentrations, deferiprone and deferasirox significantly reduced the catecholamine neurotoxicity at concentrations that are within their plasma levels following standard dosage. SIH was the most effective iron chelator to protect the cells with the lowest own toxicity of all the assayed conventional chelators. This favorable feature was even more pronounced in prochelator BSIH that does not chelate iron unless its protective group is cleaved in disease-specific oxidative stress conditions. Hence, this study demonstrated that while iron chelation may have general neuroprotective potential against catecholamine auto-oxidation and toxicity, SIH and BSIH represent promising lead molecules and warrant further studies in more complex animal models.

• MeSH
• buňky PC12 MeSH
• chelátory železa * farmakologie   MeSH
• deferasirox farmakologie   MeSH
• deferipron farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• dopamin farmakologie   MeSH
• katecholaminy farmakologie   MeSH
• krysa rodu Rattus MeSH
• oxidační stres MeSH
• oxidopamin farmakologie   MeSH
• přetížení železem * MeSH
• železo farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• chelátory železa * MeSH
• deferasirox MeSH
• deferipron MeSH
• deferoxamin MeSH
• dopamin MeSH
• katecholaminy MeSH
• oxidopamin MeSH
• železo MeSH

Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.

• Klíčová slova
• BHAPI, Cardiotoxicity, Catecholamines, HAPI, Iron chelation, Prochelator,
• MeSH
• adrenalin antagonisté a inhibitory   toxicita   MeSH
• biokatalýza MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   MeSH
• glutathion metabolismus   MeSH
• hydroxylový radikál metabolismus   MeSH
• isoprenalin antagonisté a inhibitory   toxicita   MeSH
• kardiotonika farmakologie   MeSH
• katecholaminy antagonisté a inhibitory   toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové farmakologie   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• prekurzory léčiv farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• semikarbazony farmakologie   MeSH
• sloučeniny boru farmakologie   MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adrenalin MeSH
• chelátory železa MeSH
• glutathion MeSH
• hydroxylový radikál MeSH
• isoprenalin MeSH
• kardiotonika MeSH
• katecholaminy MeSH
• kyseliny boronové MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Prohlížeč
• prekurzory léčiv MeSH
• reaktivní formy kyslíku MeSH
• semikarbazony MeSH
• sloučeniny boru MeSH
• železo MeSH

Free cellular iron catalyzes the formation of toxic hydroxyl radicals and therefore chelation of iron could be a promising therapeutic approach in pathological states associated with oxidative stress. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a strong intracellular iron chelator with well documented potential to protect against oxidative damage both in vitro and in vivo. Due to the short biological half-life of SIH and risk of toxicity due to iron depletion, boronate prochelator BSIH has been designed. BSIH cannot bind iron until it is activated by certain reactive oxygen species to active chelator SIH. The aim of this study was to examine the toxicity and cytoprotective potential of BSIH, SIH, and their decomposition products against hydrogen peroxide-induced injury of H9c2 cardiomyoblast cells. Using HPLC, we observed that salicylaldehyde was the main decomposition products of SIH and BSIH, although a small amount of salicylic acid was also detected. In the case of BSIH, the concentration of formed salicylaldehyde consistently exceeded that of SIH. Isoniazid and salicylic acid were not toxic nor did they provide any antioxidant protective effect in H9c2 cells. In contrast, salicylaldehyde was able to chelate intracellular iron and significantly preserve cellular viability and mitochondrial inner membrane potential induced by hydrogen peroxide. However it was consistently less effective than SIH. The inherent toxicities of salicylaldehyde and SIH were similar. Hence, although SIH - the active chelating agent formed following the BSIH activation - undergoes rapid hydrolysis, its principal decomposition product salicylaldehyde accounts markedly for both cytoprotective and toxic properties.

• Klíčová slova
• Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH), Iron chelation, Prochelator, Salicylaldehyde, Salicylaldehyde isonicotinoyl hydrazone (SIH),
• MeSH
• aldehydy farmakologie   toxicita   MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   toxicita   MeSH
• hydrazony farmakologie   toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové farmakologie   toxicita   MeSH
• kyseliny isonikotinové farmakologie   toxicita   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• myoblasty srdeční účinky léků   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• poločas MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• chelátory železa MeSH
• hydrazony MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• peroxid vodíku MeSH
• reaktivní formy kyslíku MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• železo MeSH

Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.

• Klíčová slova
• Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone, anti-cancer agents, di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, metabolism, pharmacokinetics,
• MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• protinádorové látky metabolismus   farmakokinetika   farmakologie   MeSH
• tandemová hmotnostní spektrometrie MeSH
• thiosemikarbazony metabolismus   farmakokinetika   farmakologie   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Prohlížeč
• protinádorové látky MeSH
• thiosemikarbazony MeSH

Salicylaldehyde isonicotinoyl hydrazone (SIH) is an intracellular iron chelator with well documented potential to protect against oxidative injury both in vitro and in vivo. However, it suffers from short biological half-life caused by fast hydrolysis of the hydrazone bond. Recently, a concept of boronate prochelators has been introduced as a strategy that might overcome these limitations. This study presents two complementary analytical methods for detecting the prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone-BSIH along with its active metal-binding chelator SIH in different solution matrices and concentration ranges. An LC-UV method for determination of BSIH and SIH in buffer and cell culture medium was validated over concentrations of 7-115 and 4-115 μM, respectively, and applied to BSIH activation experiments in vitro. An LC-MS assay was validated for quantification of BSIH and SIH in plasma over the concentration range of 0.06-23 and 0.24-23 μM, respectively, and applied to stability studies in plasma in vitro as well as analysis of plasma taken after i.v. administration of BSIH to rats. A Zorbax-RP bonus column and mobile phases containing either phosphate buffer with EDTA or ammonium formate and methanol/acetonitrile mixture provided suitable conditions for the LC-UV and LC-MS analysis, respectively. Samples were diluted or precipitated with methanol prior to analysis. These separative analytical techniques establish the first validated protocols to investigate BSIH activation by hydrogen peroxide in multiple matrices, directly compare the stabilities of the prochelator and its chelator in plasma, and provide the first basic pharmacokinetic data of this prochelator. Experiments reveal that BSIH is stable in all media tested and is partially converted to SIH by H2O2. The observed integrity of BSIH in plasma samples from the in vivo study suggests that the concept of prochelation might be a promising strategy for further development of aroylhydrazone cytoprotective agents.

• Klíčová slova
• Aroylhydrazone, Boronyl salicylaldehyde isonicotinoyl hydrazone, Pharmacokinetics, Prochelator salicylaldehyde isonicotinoyl hydrazone, Stability,
• MeSH
• aldehydy analýza   krev   MeSH
• chelátory analýza   MeSH
• chromatografie kapalinová metody   MeSH
• hmotnostní spektrometrie metody   MeSH
• hydrazony analýza   krev   MeSH
• kultivační média chemie   MeSH
• kyseliny boronové analýza   krev   MeSH
• kyseliny isonikotinové analýza   krev   MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• referenční standardy MeSH
• senzitivita a specificita MeSH
• spektrofotometrie ultrafialová metody   MeSH
• stabilita léku MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• chelátory MeSH
• hydrazony MeSH
• kultivační média MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

• MeSH
• aldehydy chemie   farmakologie   toxicita   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• hydrazony chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myoblasty účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• protinádorové látky chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• antioxidancia MeSH
• chelátory železa MeSH
• hydrazony MeSH
• peroxid vodíku MeSH
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.

• Klíčová slova
• BSIH, Deferasirox, Free radicals, ICL670A, Iron chelation, Prochelator, Salicylaldehyde isonicotinoyl hydrazone,
• MeSH
• aldehydy chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzoáty chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• cytoprotekce * MeSH
• deferasirox MeSH
• hydrazony chemie   farmakologie   MeSH
• kardiomyocyty účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové chemie   farmakologie   MeSH
• kyseliny isonikotinové chemie   farmakologie   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• peroxid vodíku metabolismus   MeSH
• potkani Wistar MeSH
• semikarbazony chemie   farmakologie   MeSH
• sloučeniny boru chemie   farmakologie   MeSH
• srdeční mitochondrie účinky léků   fyziologie   MeSH
• triazoly chemie   farmakologie   MeSH
• železo chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• benzoáty MeSH
• chelátory železa MeSH
• deferasirox MeSH
• hydrazony MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Prohlížeč
• peroxid vodíku MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• semikarbazony MeSH
• sloučeniny boru MeSH
• triazoly MeSH
• železo MeSH

Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA-MB-231 cells. Furthermore, the synergy of NHAPI and tamoxifen was confirmed using MCF-7 cells by electrical impedance data, a mitochondrial inner membrane potential assay and cell cycle analyses. This is the first systematic investigation to quantitatively assess interactions between Fe chelators and standard chemotherapies using breast cancer cells. These studies are vital for their future clinical development.

• MeSH
• aldehydy farmakologie   MeSH
• chelátory železa farmakologie   MeSH
• cyklofosfamid analogy a deriváty   MeSH
• deferoxamin farmakologie   MeSH
• doxorubicin MeSH
• fluoruracil MeSH
• hydrazony farmakologie   MeSH
• lidé MeSH
• methotrexát MeSH
• MFC-7 buňky MeSH
• paclitaxel MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• synergismus léků MeSH
• tamoxifen MeSH
• thiosemikarbazony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• chelátory železa MeSH
• cyklofosfamid MeSH
• deferoxamin MeSH
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Prohlížeč
• doxorubicin MeSH
• fluoruracil MeSH
• hydrazony MeSH
• methotrexát MeSH
• paclitaxel MeSH
• perfosfamide MeSH Prohlížeč
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• tamoxifen MeSH
• thiosemikarbazony MeSH

Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.

• MeSH
• antracykliny farmakologie   MeSH
• biokatalýza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• daunomycin farmakologie   MeSH
• dexrazoxan farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• glutathion metabolismus   MeSH
• glutathiondisulfid metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kaspasy metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• novorozená zvířata MeSH
• piperaziny farmakologie   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• thiobarbituráty farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• dexrazoxan MeSH
• DNA-topoisomerasy typu II MeSH
• doxorubicin MeSH
• glutathion MeSH
• glutathiondisulfid MeSH
• inhibitory topoisomerasy II MeSH
• kaspasy MeSH
• merbarone MeSH Prohlížeč
• piperaziny MeSH
• sobuzoxane MeSH Prohlížeč
• thiobarbituráty MeSH

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

• MeSH
• antioxidancia chemie   farmakologie   MeSH
• antracykliny škodlivé účinky   chemie   farmakologie   MeSH
• chelátory škodlivé účinky   chemie   farmakologie   MeSH
• kardiotonika škodlivé účinky   chemie   farmakologie   MeSH
• kovy škodlivé účinky   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres * MeSH
• protinádorové látky škodlivé účinky   chemie   farmakologie   MeSH
• razoxan škodlivé účinky   chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce * MeSH
• srdce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• antracykliny MeSH
• chelátory MeSH
• kardiotonika MeSH
• kovy MeSH
• protinádorové látky MeSH
• razoxan MeSH
• reaktivní formy kyslíku MeSH