Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Cardioprotective Potential of Iron Chelators and Prochelators

Author(s): Hana Jansová and Tomáś Šimůnek*

Volume 26 , Issue 2 , 2019

Page: [288 - 301] Pages: 14

DOI: 10.2174/0929867324666170920155439

Price: $58


Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron chelators have been studied in various cardiovascular disorders with known or presumed oxidative stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine suffers from poor plasma membrane permeability, which means that high and clinically unachievable concentrations/doses must be employed to obtain cardioprotection. Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for this purpose, particularly in states without systemic iron overload. Apart from agents that are already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl hydrazone (SIH), have provided promising results. However, the use of classical iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion. Recent studies have therefore focused on "masked" prochelators that have little or no affinity for iron until site-specific activation by reactive oxygen species.

Keywords: Cardioprotection, iron chelators, iron prochelators, oxidative stress, anthracyclines, cardiotoxicity.

Kakhlon, O.; Cabantchik, Z.I. The labile iron pool: Characterization, measurement, and participation in cellular processes. Free Radic. Biol. Med., 2002, 33(8), 1037-1046.
Crichton, R.; Boelaert, J.R.; Braun, V.; Hantke, K.; Marx, J.J.M.; Santos, M.; Ward, R. Inorg. Biochem. Iron Metab; John Wiley & Sons, 2001.
Halliwell, B. Biochemistry of oxidative stress. Biochem. Soc. Trans., 2007, 35(Pt 5), 1147-1150.
Jomova, K.; Valko, M. Advances in metal-induced oxidative stress and human disease. Toxicology, 2011, 283(2-3), 65-87.
Horwitz, L.D.; Rosenthal, E.A. Iron-mediated cardiovascular injury. Vasc. Med., 1999, 4(2), 93-99.
Trinder, D.; Fox, C.; Vautier, G.; Olynyk, J.K. Molecular pathogenesis of iron overload. Gut, 2002, 51(2), 290-295.
Kremastinos, D.T.; Farmakis, D. Iron overload cardiomyopathy in clinical practice. Circulation, 2011, 124(20), 2253-2263.
Weidemann, F.; Rummey, C.; Bijnens, B.; Stork, S.; Jasaityte, R.; Dhooge, J.; Baltabaeva, A.; Sutherland, G.; Schulz, J.B.; Meier, T. Mitochondrial Protection With Idebenone In Cardiac Or Neurological Outcome Study, G. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation, 2012, 125(13), 1626-1634.
Perrelli, M.G.; Pagliaro, P.; Penna, C. Ischemia/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species. World J. Cardiol., 2011, 3(6), 186-200.
Horwitz, L.D.; Leff, J.A. Catalase and hydrogen peroxide cytotoxicity in cultured cardiac myocytes. J. Mol. Cell. Cardiol., 1995, 27(3), 909-915.
Reif, D.W. Ferritin as a source of iron for oxidative damage. Free Radic. Biol. Med., 1992, 12(5), 417-427.
Mladenka, P.; Simunek, T.; Hubl, M.; Hrdina, R. The role of reactive oxygen and nitrogen species in cellular iron metabolism. Free Radic. Res., 2006, 40(3), 263-272.
Kiechl, S.; Willeit, J.; Egger, G.; Poewe, W.; Oberhollenzer, F. Body iron stores and the risk of carotid atherosclerosis: Prospective results from the Bruneck study. Circulation, 1997, 96(10), 3300-3307.
Kraml, P. The role of iron in the pathogenesis of atherosclerosis. Physiol. Res., 2017, 66(Suppl. 1), S55-S67.
Simunek, T.; Sterba, M.; Popelova, O.; Adamcova, M.; Hrdina, R.; Gersl, V. Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol. Rep., 2009, 61(1), 154-171.
Hrdina, R.; Gersl, V.; Klimtova, I.; Simunek, T.; Machackova, J.; Adamcova, M. Anthracycline-induced cardiotoxicity. Acta Med. (Hradec Kralove), 2000, 43(3), 75-82.
Hershko, C.; Link, G.; Tzahor, M.; Kaltwasser, J.P.; Athias, P.; Grynberg, A.; Pinson, A. Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: Studies in rat heart cells in culture. J. Lab. Clin. Med., 1993, 122(3), 245-251.
Lipshultz, S.E.; Lipsitz, S.R.; Kutok, J.L.; Miller, T.L.; Colan, S.D.; Neuberg, D.S.; Stevenson, K.E.; Fleming, M.D.; Sallan, S.E.; Franco, V.I.; Henkel, J.M.; Asselin, B.L.; Athale, U.H.; Clavell, L.A.; Michon, B.; Laverdiere, C.; Larsen, E.; Kelly, K.M.; Silverman, L.B. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer, 2013, 119(19), 3555-3562.
Mann, D.L.; Kent, R.L.; Parsons, B.; Cooper, G. m 4th. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation, 1992, 85(2), 790-804.
Dhalla, N.S.; Adameova, A.; Kaur, M. Role of catecholamine oxidation in sudden cardiac death. Fundam. Clin. Pharmacol., 2010, 24(5), 539-546.
Osteraas, N.D.; Lee, V.H. Neurocardiology. Handb. Clin. Neurol., 2017, 140, 49-65.
Costa, V.M.; Carvalho, F.; Bastos, M.L.; Carvalho, R.A.; Carvalho, M.; Remiao, F. Contribution of catecholamine reactive intermediates and oxidative stress to the pathologic features of heart diseases. Curr. Med. Chem., 2011, 18(15), 2272-2314.
Hašková, P.; Kovaříková, P.; Koubková, L.; Vávrová, A.; Macková, E.; Simůnek, T. Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity. Free Radic. Biol. Med., 2011, 50(4), 537-549.
Cohen, A.R.; Galanello, R.; Pennell, D.J.; Cunningham, M.J.; Vichinsky, E. Thalassemia. Hematol-Am. Soc. Hematol. Educ. Program., 2004. 14-34.
Galey, J.B. Recent advances in the design of iron chelators against oxidative damage. Mini Rev. Med. Chem., 2001, 1(3), 233-242.
Borgna-Pignatti, C.; Cappellini, M.D.; De Stefano, P.; Del Vecchio, G.C.; Forni, G.L.; Gamberini, M.R.; Ghilardi, R.; Origa, R.; Piga, A.; Romeo, M.A.; Zhao, H.; Cnaan, A. Survival and complications in thalassemia. Ann. N. Y. Acad. Sci., 2005, 1054, 40-47.
Buss, J.L.; Torti, F.M.; Torti, S.V. The role of iron chelation in cancer therapy. Curr. Med. Chem., 2003, 10(12), 1021-1034.
Saletta, F.; Suryo Rahmanto, Y.; Noulsri, E.; Richardson, D.R. Iron chelator-mediated alterations in gene expression: Identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1 alpha and p53. Mol. Pharmacol., 2010, 77(3), 443-458.
van Asbeck, B.S.; Georgiou, N.A.; van der Bruggen, T.; Oudshoorn, M.; Nottet, H.S.; Marx, J.J. Anti-HIV effect of iron chelators: Different mechanisms involved. J. Clin. Virol., 2001, 20(3), 141-147.
Reelfs, O.; Eggleston, I.M.; Pourzand, C. Skin protection against UVA-induced iron damage by multiantioxidants and iron chelating drugs/prodrugs. Curr. Drug Metab., 2010, 11(3), 242-249.
Duffy, S.J.; Biegelsen, E.S.; Holbrook, M.; Russell, J.D.; Gokce, N.; Keaney, J.F., Jr; Vita, J.A. Iron chelation improves endothelial function in patients with coronary artery disease. Circulation, 2001, 103(23), 2799-2804.
Kwiatkowski, A.; Ryckewaert, G.; Jissendi Tchofo, P.; Moreau, C.; Vuillaume, I.; Chinnery, P.F.; Destee, A.; Defebvre, L.; Devos, D. Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. Parkinsonism Relat. Disord., 2012, 18(1), 110-112.
Salkovic-Petrisic, M.; Knezovic, A.; Osmanovic-Barilar, J.; Smailovic, U.; Trkulja, V.; Riederer, P.; Amit, T.; Mandel, S.; Youdim, M.B. Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer’s disease. Life Sci., 2015, 136, 108-119.
Ward, R.J.; Dexter, D.T.; Crichton, R.R. Neurodegenerative diseases and therapeutic strategies using iron chelators. J. Trace Elem. Med. Biol., 2015, 31, 267-273.
Chan, W.; Taylor, A.J.; Ellims, A.H.; Lefkovits, L.; Wong, C.; Kingwell, B.A.; Natoli, A.; Croft, K.D.; Mori, T.; Kaye, D.M.; Dart, A.M.; Duffy, S.J. Effect of iron chelation on myocardial infarct size and oxidative stress in ST-elevation-myocardial infarction. Circ. Cardiovasc. Interv., 2012, 5(2), 270-278.
Neckar, J.; Boudikova, A.; Mandikova, P.; Sterba, M.; Popelova, O.; Miksik, I.; Dabrowska, L.; Mraz, J.; Gersl, V.; Kolar, F. Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts. Can. J. Physiol. Pharmacol., 2012, 90(9), 1303-1310.
Kwiatkowski, J.L. Real-world use of iron chelators. Hematology (Am. Soc. Hematol. Educ. Program), 2011, 2011, 451-458.
Pennell, D.J.; Berdoukas, V.; Karagiorga, M.; Ladis, V.; Piga, A.; Aessopos, A.; Gotsis, E.D.; Tanner, M.A.; Smith, G.C.; Westwood, M.A.; Wonke, B.; Galanello, R. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood, 2006, 107(9), 3738-3744.
Galanello, R.; Kattamis, A.; Piga, A.; Fischer, R.; Leoni, G.; Ladis, V.; Voi, V.; Lund, U.; Tricta, F. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia. Haematologica, 2006, 91(9), 1241-1243.
Modell, B.; Khan, M.; Darlison, M. Survival in beta-thalassaemia major in the UK: Data from the UK Thalassaemia Register. Lancet, 2000, 355(9220), 2051-2052.
Maggio, A.; Filosa, A.; Vitrano, A.; Aloj, G.; Kattamis, A.; Ceci, A.; Fucharoen, S.; Cianciulli, P.; Grady, R.W.; Prossomariti, L.; Porter, J.B.; Iacono, A.; Cappellini, M.D.; Bonifazi, F.; Cassara, F.; Harmatz, P.; Wood, J.; Gluud, C. Iron chelation therapy in thalassemia major: A systematic review with meta-analyses of 1520 patients included on randomized clinical trials. Blood Cells Mol. Dis., 2011, 47(3), 166-175.
Farber, N.E.; Vercellotti, G.M.; Jacob, H.S.; Pieper, G.M.; Gross, G.J. Evidence for a role of iron-catalyzed oxidants in functional and metabolic stunning in the canine heart. Circ. Res., 1988, 63(2), 351-360.
Phaelante, A.; Rohde, L.E.; Lopes, A.; Olsen, V.; Tobar, S.A.; Cohen, C.; Martinelli, N.; Biolo, A.; Dal-Pizzol, F.; Clausell, N.; Andrades, M. N-acetylcysteine plus deferoxamine improves cardiac function in wistar rats after non-reperfused acute myocardial infarction. J. Cardiovasc. Transl. Res., 2015, 8(5), 328-337.
Ryter, S.W.; Si, M.; Lai, C.C.; Su, C.Y. Regulation of endothelial heme oxygenase activity during hypoxia is dependent on chelatable iron. Am. J. Physiol. Heart Circ. Physiol., 2000, 279(6), H2889-H2897.
Reddy, B.R.; Wynne, J.; Kloner, R.A.; Przyklenk, K. Pretreatment with the iron chelator desferrioxamine fails to provide sustained protection against myocardial ischaemia-reperfusion injury. Cardiovasc. Res., 1991, 25(9), 711-718.
Bendova, P.; Mackova, E.; Haskova, P.; Vavrova, A.; Jirkovsky, E.; Sterba, M.; Popelova, O.; Kalinowski, D.S.; Kovarikova, P.; Vavrova, K.; Richardson, D.R.; Simunek, T. Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury. Chem. Res. Toxicol., 2010, 23(6), 1105-1114.
Haskova, P.; Koubkova, L.; Vavrova, A.; Mackova, E.; Hruskova, K.; Kovarikova, P.; Vavrova, K.; Simunek, T. Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity. Toxicology, 2011, 289(2-3), 122-131.
El-Demerdash, E.; Mohamadin, A.M. Does oxidative stress contribute in tricyclic antidepressants-induced cardiotoxicity? Toxicol. Lett., 2004, 152(2), 159-166.
Dobsak, P.; Siegelova, J.; Wolf, J.E.; Rochette, L.; Eicher, J.C.; Vasku, J.; Kuchtickova, S.; Horky, M. Prevention of apoptosis by deferoxamine during 4 hours of cold cardioplegia and reperfusion: In vitro study of isolated working rat heart model. Pathophysiology, 2002, 9(1), 27.
Saad, S.Y.; Najjar, T.A.; Al-Rikabi, A.C. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol. Res., 2001, 43(3), 211-218.
Voest, E.E.; van Acker, S.A.; van der Vijgh, W.J.; van Asbeck, B.S.; Bast, A. Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity. J. Mol. Cell. Cardiol., 1994, 26(9), 1179-1185.
Herman, E.H.; Zhang, J.; Ferrans, V.J. Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer Chemother. Pharmacol., 1994, 35(2), 93-100.
Hassan, M.A.; Tolba, O.A. Iron chelation monotherapy in transfusion-dependent beta-thalassemia major patients: A comparative study of deferasirox and deferoxamine. Electron. Physician, 2016, 8(5), 2425-2431.
Ryals, B.; Westbrook, E.; Schacht, J. Morphological evidence of ototoxicity of the iron chelator deferoxamine. Hear. Res., 1997, 112(1-2), 44-48.
Beresewicz, A.; Horackova, M. Alterations in electrical and contractile behavior of isolated cardiomyocytes by hydrogen peroxide: Possible ionic mechanisms. J. Mol. Cell. Cardiol., 1991, 23(8), 899-918.
Hoffbrand, A.V.; Cohen, A.; Hershko, C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood, 2003, 102(1), 17-24.
Anderson, L.J.; Wonke, B.; Prescott, E.; Holden, S.; Walker, J.M.; Pennell, D.J. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet, 2002, 360(9332), 516-520.
Piga, A.; Gaglioti, C.; Fogliacco, E.; Tricta, F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica, 2003, 88(5), 489-496.
Borgna-Pignatti, C.; Cappellini, M.D.; De Stefano, P.; Del Vecchio, G.C.; Forni, G.L.; Gamberini, M.R.; Ghilardi, R.; Piga, A.; Romeo, M.A.; Zhao, H.; Cnaan, A. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood, 2006, 107(9), 3733-3737.
Tanner, M.A.; Galanello, R.; Dessi, C.; Smith, G.C.; Westwood, M.A.; Agus, A.; Roughton, M.; Assomull, R.; Nair, S.V.; Walker, J.M.; Pennell, D.J. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation, 2007, 115(14), 1876-1884.
van der Kraaij, A.M.; van Eijk, H.G.; Koster, J.F. Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and the antioxidant (+)-cyanidanol-3. Circulation, 1989, 80(1), 158-164.
Barnabe, N.; Zastre, J.A.; Venkataram, S.; Hasinoff, B.B. Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radic. Biol. Med., 2002, 33(2), 266-275.
Link, G.; Tirosh, R.; Pinson, A.; Hershko, C. Role of iron in the potentiation of anthracycline cardiotoxicity: Identification of heart cell mitochondria as a major site of iron-anthracycline interaction. J. Lab. Clin. Med., 1996, 127(3), 272-278.
Xu, L.J.; Jin, L.; Pan, H.; Zhang, A.Z.; Wei, G.; Li, P.P.; Lu, W.Y. Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin. Acta Pharmacol. Sin., 2006, 27(10), 1333-1339.
Popelova, O.; Sterba, M.; Simunek, T.; Mazurova, Y.; Guncova, I.; Hroch, M.; Adamcova, M.; Gersl, V. Deferiprone does not protect against chronic anthracycline cardiotoxicity in vivo. J. Pharmacol. Exp. Ther., 2008, 326(1), 259-269.
Cohen, A.R.; Galanello, R.; Piga, A.; De Sanctis, V.; Tricta, F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood, 2003, 102(5), 1583-1587.
Waldmeier, P.C.; Buchle, A.M.; Steulet, A.F. Inhibition of catechol-O-methyltransferase (COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo. Biochem. Pharmacol., 1993, 45(12), 2417-2424.
Hershko, C.; Konijn, A.M.; Nick, H.P.; Breuer, W.; Cabantchik, Z.I.; Link, G. ICL670A: a new synthetic oral chelator: Evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood, 2001, 97(4), 1115-1122.
Wood, J.C.; Kang, B.P.; Thompson, A.; Giardina, P.; Harmatz, P.; Glynos, T.; Paley, C.; Coates, T.D. The effect of deferasirox on cardiac iron in thalassemia major: Impact of total body iron stores. Blood, 2010, 116(4), 537-543.
Taher, A.; Cappellini, M.D. Update on the use of deferasirox in the management of iron overload. Ther. Clin. Risk Manag., 2009, 5, 857-868.
Pennell, D.J.; Porter, J.B.; Cappellini, M.D.; El-Beshlawy, A.; Chan, L.L.; Aydinok, Y.; Elalfy, M.S.; Sutcharitchan, P.; Li, C.K.; Ibrahim, H.; Viprakasit, V.; Kattamis, A.; Smith, G.; Habr, D.; Domokos, G.; Roubert, B.; Taher, A. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood, 2010, 115(12), 2364-2371.
Glickstein, H.; El, R.B.; Link, G.; Breuer, W.; Konijn, A.M.; Hershko, C.; Nick, H.; Cabantchik, Z.I. Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences. Blood, 2006, 108(9), 3195-3203.
Al-Rousan, R.M.; Paturi, S.; Laurino, J.P.; Kakarla, S.K.; Gutta, A.K.; Walker, E.M.; Blough, E.R. Deferasirox removes cardiac iron and attenuates oxidative stress in the iron-overloaded gerbil. Am. J. Hematol., 2009, 84(9), 565-570.
Lal, A.; Porter, J.; Sweeters, N.; Ng, V.; Evans, P.; Neumayr, L.; Kurio, G.; Harmatz, P.; Vichinsky, E. Combined chelation therapy with deferasirox and deferoxamine in thalassemia. Blood Cells Mol. Dis., 2013, 50(2), 99-104.
Aydinok, Y.; Kattamis, A.; Cappellini, M.D.; El-Beshlawy, A.; Origa, R.; Elalfy, M.; Kilinc, Y.; Perrotta, S.; Karakas, Z.; Viprakasit, V.; Habr, D.; Constantinovici, N.; Shen, J.; Porter, J.B. Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload. Blood, 2015, 125(25), 3868-3877.
Jansová, H.; Macháček, M.; Wang, Q.; Hašková, P.; Jirkovská, A.; Potůčková, E.; Kielar, F.; Franz, K.J.; Simůnek, T. Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury. Free Radic. Biol. Med., 2014, 74, 210-221.
Hasinoff, B.B.; Patel, D.; Wu, X. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radic. Biol. Med., 2003, 35(11), 1469-1479.
Hoffbrand, A.V.; Taher, A.; Cappellini, M.D. How I treat transfusional iron overload. Blood, 2012, 120(18), 3657-3669.
FDA. Calcium Disodium Versenate - NDA 8-922/S-016.
CDC Deaths associated with hypocalcemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005. MMWR Morb. Mortal. Wkly. Rep., 2006, 55(8), 204-207.
Ibad, A.; Khalid, R.; Thompson, P.D. Chelation therapy in the treatment of cardiovascular diseases. J. Clin. Lipidol., 2016, 10(1), 58-62.
Lamas, G.A.; Ackermann, A. Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? Am. Heart J., 2000, 140(1), 4-5.
Green, D.J.; O’Driscoll, J.G.; Maiorana, A.; Scrimgeour, N.B.; Weerasooriya, R.; Taylor, R.R. Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. Clin. Exp. Pharmacol. Physiol., 1999, 26(11), 853-856.
Knudtson, M.L.; Wyse, D.G.; Galbraith, P.D.; Brant, R.; Hildebrand, K.; Paterson, D.; Richardson, D.; Burkart, C.; Burgess, E. PATCH Investigators. Chelation therapy for ischemic heart disease: A randomized controlled trial. JAMA, 2002, 287(4), 481-486.
Ernst, E. Chelation therapy for coronary heart disease: An overview of all clinical investigations. Am. Heart J., 2000, 140(1), 139-141.
Ouyang, P.; Gottlieb, S.H.; Culotta, V.L.; Navas-Acien, A. EDTA Chelation Therapy to Reduce Cardiovascular Events in Persons with Diabetes. Curr. Cardiol. Rep., 2015, 17(11), 96.
Wirebaugh, S.R.; Geraets, D.R. Apparent failure of edetic acid chelation therapy for the treatment of coronary atherosclerosis. Ann. Pharmacother., 1990, 24(1), 22-25.
Shrihari, J.S.; Roy, A.; Prabhakaran, D.; Reddy, K.S. Role of EDTA chelation therapy in cardiovascular diseases. Natl. Med. J. India, 2006, 19(1), 24-26.
Seely, D.M.; Wu, P.; Mills, E.J. EDTA chelation therapy for cardiovascular disease: A systematic review. BMC Cardiovasc. Disord., 2005, 5, 32.
Lamas, G.A.; Goertz, C.; Boineau, R.; Mark, D.B.; Rozema, T.; Nahin, R.L.; Lindblad, L.; Lewis, E.F.; Drisko, J.; Lee, K.L. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: The TACT randomized trial. JAMA, 2013, 309(12), 1241-1250.
Guldager, B.; Brixen, K.T.; Jorgensen, S.J.; Nielsen, H.K.; Mosekilde, L.; Jelnes, R. Effects of intravenous EDTA treatment on serum parathyroid hormone (1-84) and biochemical markers of bone turnover. Dan. Med. Bull., 1993, 40(5), 627-630.
Richardson, D.R.; Ponka, P. Pyridoxal isonicotinoyl hydrazone and its analogs: Potential orally effective iron-chelating agents for the treatment of iron overload disease. J. Lab. Clin. Med., 1998, 131(4), 306-315.
Richardson, D.R.; Baker, E. The release of iron and transferrin from the human melanoma cell. Biochim. Biophys. Acta, 1991, 1091(3), 294-302.
Richardson, D.R.; Hefter, G.T.; May, P.M.; Webb, J.; Baker, E. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. III. Formation constants with calcium(II), magnesium(II) and zinc(II). Biol. Met., 1989, 2(3), 161-167.
Richardson, D.R. Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process. Biochim. Biophys. Acta, 1997, 1320(1), 45-57.
Brittenham, G.M. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin. Hematol., 1990, 27(2), 112-116.
Buss, J.L.; Ponka, P. Hydrolysis of pyridoxal isonicotinoyl hydrazone and its analogs. Biochim. Biophys. Acta, 2003, 1619(2), 177-186.
Whitnall, M.; Suryo Rahmanto, Y.; Sutak, R.; Xu, X.; Becker, E.M.; Mikhael, M.R.; Ponka, P.; Richardson, D.R. The MCK mouse heart model of Friedreich’s ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc. Natl. Acad. Sci. USA, 2008, 105(28), 9757-9762.
Simunek, T.; Klimtova, I.; Kaplanova, J.; Sterba, M.; Mazurova, Y.; Adamcova, M.; Hrdina, R.; Gersl, V.; Ponka, P. Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits. Pharmacol. Res., 2005, 51(3), 223-231.
Buss, J.L.; Hermes-Lima, M.; Ponka, P. Pyridoxal isonicotinoyl hydrazone and its analogues. Adv. Exp. Med. Biol., 2002, 509, 205-229.
Simunek, T.; Boer, C.; Bouwman, R.A.; Vlasblom, R.; Versteilen, A.M.; Sterba, M.; Gersl, V.; Hrdina, R.; Ponka, P.; de Lange, J.J.; Paulus, W.J.; Musters, R.J. SIH--a novel lipophilic iron chelator--protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death. J. Mol. Cell. Cardiol., 2005, 39(2), 345-354.
Horackova, M.; Ponka, P.; Byczko, Z. The antioxidant effects of a novel iron chelator salicylaldehyde isonicotinoyl hydrazone in the prevention of H(2)O(2) injury in adult cardiomyocytes. Cardiovasc. Res., 2000, 47(3), 529-536.
Simunek, T.; Sterba, M.; Popelova, O.; Kaiserova, H.; Adamcova, M.; Hroch, M.; Haskova, P.; Ponka, P.; Gersl, V. Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone. Br. J. Pharmacol., 2008, 155(1), 138-148.
Sterba, M.; Popelová, O.; Simůnek, T.; Mazurová, Y.; Potácová, A.; Adamcová, M.; Guncová, I.; Kaiserová, H.; Palicka, V.; Ponka, P.; Gersl, V. Iron chelation-afforded cardioprotection against chronic anthracycline cardiotoxicity: A study of salicylaldehyde isonicotinoyl hydrazone (SIH). Toxicology, 2007, 235(3), 150-166.
Sterba, M.; Popelova, O.; Simunek, T.; Mazurova, Y.; Potacova, A.; Adamcova, M.; Kaiserova, H.; Ponka, P.; Gersl, V. Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity. J. Pharmacol. Exp. Ther., 2006, 319(3), 1336-1347.
Kovarikova, P.; Klimes, J.; Sterba, M.; Popelova, O.; Mokry, M.; Gersl, V.; Ponka, P. Development of high-performance liquid chromatographic determination of salicylaldehyde isonicotinoyl hydrazone in rabbit plasma and application of this method to an in vivo study. J. Sep. Sci., 2005, 28(12), 1300-1306.
Hruskova, K.; Kovarikova, P.; Bendova, P.; Haskova, P.; Mackova, E.; Stariat, J.; Vavrova, A.; Vavrova, K.; Simunek, T. Synthesis and initial in vitro evaluations of novel antioxidant aroylhydrazone iron chelators with increased stability against plasma hydrolysis. Chem. Res. Toxicol., 2011, 24(3), 290-302.
Hruskova, K.; Potuckova, E.; Hergeselova, T.; Liptakova, L.; Haskova, P.; Mingas, P.; Kovarikova, P.; Simunek, T.; Vavrova, K. Aroylhydrazone iron chelators: Tuning antioxidant and antiproliferative properties by hydrazide modifications. Eur. J. Med. Chem., 2016, 120, 97-110.
Richardson, D.R.; Bernhardt, P.V. Crystal and molecular structure of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and its iron(III) complex: An iron chelator with anti-tumour activity. J. Biol. Inorg. Chem., 1999, 4(3), 266-273.
Merlot, A.M.; Kalinowski, D.S.; Richardson, D.R. Novel chelators for cancer treatment: Where are we now? Antioxid. Redox Signal., 2013, 18(8), 973-1006.
Kalinowski, D.S.; Richardson, D.R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev., 2005, 57(4), 547-583.
Rao, V.A.; Zhang, J.; Klein, S.R.; Espandiari, P.; Knapton, A.; Dickey, J.S.; Herman, E.; Shacter, E.B. The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. Cancer Chemother. Pharmacol., 2011, 68(5), 1125-1134.
Hasinoff, B.B.; Patel, D. The iron chelator Dp44mT does not protect myocytes against doxorubicin. J. Inorg. Biochem., 2009, 103(7), 1093-1101.
Whitnall, M.; Howard, J.; Ponka, P.; Richardson, D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl. Acad. Sci. USA, 2006, 103(40), 14901-14906.
Kovacevic, Z.; Chikhani, S.; Lovejoy, D.B.; Richardson, D.R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: A new strategy for the treatment of pancreatic cancer. Mol. Pharmacol., 2011, 80(4), 598-609.
Lovejoy, D.B.; Sharp, D.M.; Seebacher, N.; Obeidy, P.; Prichard, T.; Stefani, C.; Basha, M.T.; Sharpe, P.C.; Jansson, P.J.; Kalinowski, D.S.; Bernhardt, P.V.; Richardson, D.R. Novel second-generation di-2-pyridylketone thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous administration in vivo. J. Med. Chem., 2012, 55(16), 7230-7244.
Sestak, V.; Stariat, J.; Cermanova, J.; Potuckova, E.; Chladek, J.; Roh, J.; Bures, J.; Jansova, H.; Prusa, P.; Sterba, M.; Micuda, S.; Simunek, T.; Kalinowski, D.S.; Richardson, D.R.; Kovarikova, P. Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents. Oncotarget, 2015, 6(40), 42411-42428.
Mladenka, P.; Macakova, K.; Filipsky, T.; Zatloukalova, L.; Jahodar, L.; Bovicelli, P.; Silvestri, I.P.; Hrdina, R.; Saso, L. In vitro analysis of iron chelating activity of flavonoids. J. Inorg. Biochem., 2011, 105(5), 693-701.
Mladenka, P.; Zatloukalova, L.; Filipsky, T.; Hrdina, R. Cardiovascular effects of flavonoids are not caused only by direct antioxidant activity. Free Radic. Biol. Med., 2010, 49(6), 963-975.
Randive, K.H.; Jaishree, V.; Patil, K.S.; Patil, K. Synthesis and biological evaluation of novel coumarin derivatives as antioxidant agents. Bioorg. Khim., 2015, 41(3), 366-374.
Mladenka, P.; Macakova, K.; Zatloukalova, L.; Rehakova, Z.; Singh, B.K.; Prasad, A.K.; Parmar, V.S.; Jahodar, L.; Hrdina, R.; Saso, L. In vitro interactions of coumarins with iron. Biochimie, 2010, 92(9), 1108-1114.
Kathuria, A.; Priya, N.; Chand, K.; Singh, P.; Gupta, A.; Jalal, S.; Gupta, S.; Raj, H.G.; Sharma, S.K. Substrate specificity of acetoxy derivatives of coumarins and quinolones towards Calreticulin mediated transacetylation: Investigations on antiplatelet function. Bioorg. Med. Chem., 2012, 20(4), 1624-1638.
Filipsky, T.; Riha, M.; Macakova, K.; Anzenbacherova, E.; Karlickova, J.; Mladenka, P. Antioxidant effects of coumarins include direct radical scavenging, metal chelation and inhibition of ROS-producing enzymes. Curr. Top. Med. Chem., 2015, 15(5), 415-431.
Najmanova, I.; Dosedel, M.; Hrdina, R.; Anzenbacher, P.; Filipsky, T.; Riha, M.; Mladenka, P. Cardiovascular effects of coumarins besides their antioxidant activity. Curr. Top. Med. Chem., 2015, 15(9), 830-849.
Lonnerdal, B.; Iyer, S. Lactoferrin: Molecular structure and biological function. Annu. Rev. Nutr., 1995, 15, 93-110.
Mladenka, P.; Semecky, V.; Bobrovova, Z.; Nachtigal, P.; Vavrova, J.; Holeckova, M.; Palicka, V.; Mazurova, Y.; Hrdina, R. The effects of lactoferrin in a rat model of catecholamine cardiotoxicity. Biometals, 2009, 22(2), 353-361.
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Jarvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
Oliveri, V.; Vecchio, G. Prochelator strategies for site-selective activation of metal chelators. J. Inorg. Biochem., 2016, 162, 31-43.
Charkoudian, L.K.; Pham, D.M.; Kwon, A.M.; Vangeloff, A.D.; Franz, K.J. Modifications of boronic ester pro-chelators triggered by hydrogen peroxide tune reactivity to inhibit metal-promoted oxidative stress. Dalton Trans., 2007, 43, 5031-5042.
Kielar, F.; Helsel, M.E.; Wang, Q.; Franz, K.J. Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation. Metallomics, 2012, 4(9), 899-909.
Charkoudian, L.K.; Dentchev, T.; Lukinova, N.; Wolkow, N.; Dunaief, J.L.; Franz, K.J. Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide. J. Inorg. Biochem., 2008, 102(12), 2130-2135.
Simon, J.; Salzbrunn, S.; Prakash, G.K.; Petasis, N.A.; Olah, G.A. Regioselective conversion of arylboronic acids to phenols and subsequent coupling to symmetrical diaryl ethers. J. Org. Chem., 2001, 66(2), 633-634.
Jansova, H.; Bures, J.; Machacek, M.; Haskova, P.; Jirkovska, A.; Roh, J.; Wang, Q.; Franz, K.J.; Kovarikova, P.; Simunek, T. Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products. Toxicology, 2016, 350-352, 15-24.
Bureš, J.; Jansová, H.; Stariat, J.; Filipský, T.; Mladěnka, P.; Šimůnek, T.; Kučera, R.; Klimeš, J.; Wang, Q.; Franz, K.J.; Kovaříková, P. LC-UV/MS methods for the analysis of prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH). J. Pharm. Biomed. Anal., 2015, 105, 55-63.
Charkoudian, L.K.; Pham, D.M.; Franz, K.J. A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation. J. Am. Chem. Soc., 2006, 128(38), 12424-12425.
Swain, S.M.; Vici, P. The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J. Cancer Res. Clin. Oncol., 2004, 130(1), 1-7.
Hasinoff, B.B. The interaction of the cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yL)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents Actions, 1989, 26(3-4), 378-385.
Deng, S.; Yan, T.; Jendrny, C.; Nemecek, A.; Vincetic, M.; Godtel-Armbrust, U.; Wojnowski, L. Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms. BMC Cancer, 2014, 14, 842.
Lyu, Y.L.; Kerrigan, J.E.; Lin, C.P.; Azarova, A.M.; Tsai, Y.C.; Ban, Y.; Liu, L.F. Topoisomerase IIbeta mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res., 2007, 67(18), 8839-8846.
Vavrova, A.; Jansova, H.; Mackova, E.; Machacek, M.; Haskova, P.; Tichotova, L.; Sterba, M.; Simunek, T. Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells. PLoS One, 2013, 8(10), e76676.
Lencova-Popelova, O.; Jirkovsky, E.; Jansova, H.; Jirkovska-Vavrova, A.; Vostatkova-Tichotova, L.; Mazurova, Y.; Adamcova, M.; Chladek, J.; Hroch, M.; Pokorna, Z.; Gersl, V.; Simunek, T.; Sterba, M. Cardioprotective effects of inorganic nitrate/nitrite in chronic anthracycline cardiotoxicity: Comparison with dexrazoxane. J. Mol. Cell. Cardiol., 2016, 91, 92-103.
Hasinoff, B.B. Dexrazoxane (ICRF-187) protects cardiac myocytes against hypoxia-reoxygenation damage. Cardiovasc. Toxicol., 2002, 2(2), 111-118.
Zatloukalova, L.; Filipsky, T.; Mladenka, P.; Semecky, V.; Macakova, K.; Holeckova, M.; Vavrova, J.; Palicka, V.; Hrdina, R. Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity. Can. J. Physiol. Pharmacol., 2012, 90(4), 473-484.

Rights & Permissions Print Export Cite as
Article Metrics
Related Journals
Related eBooks