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
• PC12 Cells MeSH
• Iron Chelating Agents * pharmacology   MeSH
• Deferasirox pharmacology   MeSH
• Deferiprone pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Dopamine pharmacology   MeSH
• Catecholamines pharmacology   MeSH
• Rats MeSH
• Oxidative Stress MeSH
• Oxidopamine pharmacology   MeSH
• Iron Overload * MeSH
• Iron pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Iron Chelating Agents * MeSH
• Deferasirox MeSH
• Deferiprone MeSH
• Deferoxamine MeSH
• Dopamine MeSH
• Catecholamines MeSH
• Oxidopamine MeSH
• Iron 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.

• Keywords
• BHAPI, Cardiotoxicity, Catecholamines, HAPI, Iron chelation, Prochelator,
• MeSH
• Epinephrine antagonists & inhibitors   toxicity   MeSH
• Biocatalysis MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   MeSH
• Glutathione metabolism   MeSH
• Hydroxyl Radical metabolism   MeSH
• Isoproterenol antagonists & inhibitors   toxicity   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Catecholamines antagonists & inhibitors   toxicity   MeSH
• Rats MeSH
• Boronic Acids pharmacology   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Prodrugs pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Semicarbazones pharmacology   MeSH
• Boron Compounds pharmacology   MeSH
• Iron chemistry   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Epinephrine MeSH
• Iron Chelating Agents MeSH
• Glutathione MeSH
• Hydroxyl Radical MeSH
• Isoproterenol MeSH
• Cardiotonic Agents MeSH
• Catecholamines MeSH
• Boronic Acids MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Browser
• Prodrugs MeSH
• Reactive Oxygen Species MeSH
• Semicarbazones MeSH
• Boron Compounds MeSH
• Iron 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.

• Keywords
• Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH), Iron chelation, Prochelator, Salicylaldehyde, Salicylaldehyde isonicotinoyl hydrazone (SIH),
• MeSH
• Aldehydes pharmacology   toxicity   MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   toxicity   MeSH
• Hydrazones pharmacology   toxicity   MeSH
• Rats MeSH
• Boronic Acids pharmacology   toxicity   MeSH
• Isonicotinic Acids pharmacology   toxicity   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Myoblasts, Cardiac drug effects   metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide toxicity   MeSH
• Half-Life MeSH
• Reactive Oxygen Species metabolism   MeSH
• Cell Survival drug effects   MeSH
• Chromatography, High Pressure Liquid MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Iron Chelating Agents MeSH
• Hydrazones MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• Hydrogen Peroxide MeSH
• Reactive Oxygen Species MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Iron 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.

• Keywords
• 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
• Rats MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Rats, Wistar MeSH
• Drug Evaluation, Preclinical MeSH
• Antineoplastic Agents metabolism   pharmacokinetics   pharmacology   MeSH
• Tandem Mass Spectrometry MeSH
• Thiosemicarbazones metabolism   pharmacokinetics   pharmacology   MeSH
• Chromatography, High Pressure Liquid MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Browser
• Antineoplastic Agents MeSH
• Thiosemicarbazones 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.

• Keywords
• Aroylhydrazone, Boronyl salicylaldehyde isonicotinoyl hydrazone, Pharmacokinetics, Prochelator salicylaldehyde isonicotinoyl hydrazone, Stability,
• MeSH
• Aldehydes analysis   blood   MeSH
• Chelating Agents analysis   MeSH
• Chromatography, Liquid methods   MeSH
• Mass Spectrometry methods   MeSH
• Hydrazones analysis   blood   MeSH
• Culture Media chemistry   MeSH
• Boronic Acids analysis   blood   MeSH
• Isonicotinic Acids analysis   blood   MeSH
• Molecular Structure MeSH
• Rats, Wistar MeSH
• Reference Standards MeSH
• Sensitivity and Specificity MeSH
• Spectrophotometry, Ultraviolet methods   MeSH
• Drug Stability MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Chelating Agents MeSH
• Hydrazones MeSH
• Culture Media MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser

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
• Aldehydes chemistry   pharmacology   toxicity   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Cell Line MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Hydrazones chemistry   pharmacology   toxicity   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Myoblasts drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide toxicity   MeSH
• Antineoplastic Agents chemistry   toxicity   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• Antioxidants MeSH
• Iron Chelating Agents MeSH
• Hydrazones MeSH
• Hydrogen Peroxide MeSH
• Antineoplastic Agents MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser

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.

• Keywords
• BSIH, Deferasirox, Free radicals, ICL670A, Iron chelation, Prochelator, Salicylaldehyde isonicotinoyl hydrazone,
• MeSH
• Aldehydes chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Benzoates chemistry   pharmacology   MeSH
• Cell Line MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Cytoprotection * MeSH
• Deferasirox MeSH
• Hydrazones chemistry   pharmacology   MeSH
• Myocytes, Cardiac drug effects   physiology   MeSH
• Rats MeSH
• Boronic Acids chemistry   pharmacology   MeSH
• Isonicotinic Acids chemistry   pharmacology   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Cell Membrane Permeability drug effects   MeSH
• Hydrogen Peroxide metabolism   MeSH
• Rats, Wistar MeSH
• Semicarbazones chemistry   pharmacology   MeSH
• Boron Compounds chemistry   pharmacology   MeSH
• Mitochondria, Heart drug effects   physiology   MeSH
• Triazoles chemistry   pharmacology   MeSH
• Iron chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Benzoates MeSH
• Iron Chelating Agents MeSH
• Deferasirox MeSH
• Hydrazones MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Browser
• Hydrogen Peroxide MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Semicarbazones MeSH
• Boron Compounds MeSH
• Triazoles MeSH
• Iron 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
• Aldehydes pharmacology   MeSH
• Iron Chelating Agents pharmacology   MeSH
• Cyclophosphamide analogs & derivatives   MeSH
• Deferoxamine pharmacology   MeSH
• Doxorubicin MeSH
• Fluorouracil MeSH
• Hydrazones pharmacology   MeSH
• Humans MeSH
• Methotrexate MeSH
• MCF-7 Cells MeSH
• Paclitaxel MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Drug Synergism MeSH
• Tamoxifen MeSH
• Thiosemicarbazones pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• Iron Chelating Agents MeSH
• Cyclophosphamide MeSH
• Deferoxamine MeSH
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone MeSH Browser
• Doxorubicin MeSH
• Fluorouracil MeSH
• Hydrazones MeSH
• Methotrexate MeSH
• Paclitaxel MeSH
• perfosfamide MeSH Browser
• Antineoplastic Agents MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Tamoxifen MeSH
• Thiosemicarbazones 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
• Anthracyclines pharmacology   MeSH
• Biocatalysis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Daunorubicin pharmacology   MeSH
• Dexrazoxane pharmacology   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Doxorubicin pharmacology   MeSH
• Glutathione metabolism   MeSH
• Glutathione Disulfide metabolism   MeSH
• HL-60 Cells MeSH
• Topoisomerase II Inhibitors pharmacology   MeSH
• Myocytes, Cardiac cytology   drug effects   metabolism   MeSH
• Caspases metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Drug Interactions MeSH
• Humans MeSH
• Animals, Newborn MeSH
• Piperazines pharmacology   MeSH
• Rats, Wistar MeSH
• Cell Proliferation drug effects   MeSH
• Flow Cytometry MeSH
• Thiobarbiturates pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anthracyclines MeSH
• Daunorubicin MeSH
• Dexrazoxane MeSH
• DNA Topoisomerases, Type II MeSH
• Doxorubicin MeSH
• Glutathione MeSH
• Glutathione Disulfide MeSH
• Topoisomerase II Inhibitors MeSH
• Caspases MeSH
• merbarone MeSH Browser
• Piperazines MeSH
• sobuzoxane MeSH Browser
• Thiobarbiturates 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
• Antioxidants chemistry   pharmacology   MeSH
• Anthracyclines adverse effects   chemistry   pharmacology   MeSH
• Chelating Agents adverse effects   chemistry   pharmacology   MeSH
• Cardiotonic Agents adverse effects   chemistry   pharmacology   MeSH
• Metals adverse effects   MeSH
• Humans MeSH
• Myocardium metabolism   MeSH
• Oxidation-Reduction MeSH
• Oxidative Stress * MeSH
• Antineoplastic Agents adverse effects   chemistry   pharmacology   MeSH
• Razoxane adverse effects   chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Signal Transduction * MeSH
• Heart drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH
• Anthracyclines MeSH
• Chelating Agents MeSH
• Cardiotonic Agents MeSH
• Metals MeSH
• Antineoplastic Agents MeSH
• Razoxane MeSH
• Reactive Oxygen Species MeSH