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

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

• Klíčová slova
• dysrhythmia, heart failure, hypertension, myocardial infarction, stroke,
• MeSH
• alkaloidy škodlivé účinky   MeSH
• amfetaminy škodlivé účinky   MeSH
• antiarytmika škodlivé účinky   MeSH
• antiflogistika nesteroidní škodlivé účinky   MeSH
• beta blokátory škodlivé účinky   MeSH
• blokátory kalciových kanálů škodlivé účinky   MeSH
• cévní mozková příhoda farmakoterapie   MeSH
• digoxin škodlivé účinky   MeSH
• hormony škodlivé účinky   MeSH
• kardiovaskulární nemoci chemicky indukované   farmakoterapie   MeSH
• kardiovaskulární systém účinky léků   MeSH
• kokain škodlivé účinky   MeSH
• lidé MeSH
• protinádorové látky škodlivé účinky   MeSH
• srdeční frekvence účinky léků   MeSH
• steroidy škodlivé účinky   MeSH
• vaskulární endoteliální růstový faktor A MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• alkaloidy MeSH
• amfetaminy MeSH
• antiarytmika MeSH
• antiflogistika nesteroidní MeSH
• beta blokátory MeSH
• blokátory kalciových kanálů MeSH
• cathinone MeSH Prohlížeč
• digoxin MeSH
• hormony MeSH
• kokain MeSH
• protinádorové látky MeSH
• steroidy MeSH
• vaskulární endoteliální růstový faktor A 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.

• 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

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