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

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

BACKGROUND AND PURPOSE: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stress-mediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. EXPERIMENTAL APPROACH: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H(2)O(2)) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay. KEY RESULTS: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H(2)O(2)/Fe(2+) in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H(2)O(2)/Fe(2+). Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H(2)O(2)/Fe(2+). CONCLUSIONS AND IMPLICATIONS: We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

• MeSH
• Aldehydes pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Bleomycin toxicity   MeSH
• Time Factors MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Doxorubicin toxicity   MeSH
• Electron Spin Resonance Spectroscopy MeSH
• Hydrazones pharmacology   MeSH
• Isoniazid analogs & derivatives   pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms metabolism   pathology   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide chemistry   MeSH
• Lipid Peroxidation drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antibiotics, Antineoplastic toxicity   MeSH
• Pyridoxal analogs & derivatives   pharmacology   MeSH
• Razoxane pharmacology   MeSH
• Iron Compounds chemistry   metabolism   MeSH
• Cell Survival drug effects   MeSH
• Free Radicals chemistry   MeSH
• Iron chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• Bleomycin MeSH
• Iron Chelating Agents MeSH
• Deferoxamine MeSH
• Doxorubicin MeSH
• Fenton's reagent MeSH Browser
• Hydrazones MeSH
• Isoniazid MeSH
• Hydrogen Peroxide MeSH
• Antibiotics, Antineoplastic MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Browser
• Pyridoxal MeSH
• Razoxane MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Iron Compounds MeSH
• Free Radicals MeSH
• Iron MeSH