Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity.
Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU. Instead, o-108 itself moderately inhibited cell proliferation. In vivo, chronic DAU treatment (3 mg/kg weekly for 10 weeks) induced mortality (33%), left ventricular (LV) dysfunction, a troponin T rise, and typical morphological LV damage. In contrast, all animals treated with 10 mg/kg o-108 before DAU survived without a significant drop in the LV ejection fraction (63.2 +/- 0.5 versus 59.2 +/- 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt(max)) was significantly higher than in the DAU-only group (1131 +/- 125 versus 783 +/- 53 kPa/s, p < 0.05), which corresponded with histologically assessed lower extent and intensity of myocardial damage. Although higher o-108 dose (25 mg/kg) was well tolerated when administered alone, in combination with DAU it led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. In conclusion, we show that shielding of free intracellular iron using a potent lipophilic iron chelator is able to offer a meaningful protection against chronic anthracycline cardiotoxicity. However, this approach lost its potential with the higher chelator dose, which suggests that iron might play more complex role in the pathogenesis of this disease than previously assumed.
Sterba
Martin
M
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, Hradec Králové 1, 500 38, Czech Republic. sterbam@lfhk.cuni.cz
Popelová
Olga
O
Simunek
Tomás
T
Mazurová
Yvona
Y
Potácová
Anna
A
Adamcová
Michaela
M
Kaiserová
Helena
H
Ponka
Premysl
P
Gersl
Vladimír
V
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents; D002455:Cell Division / Q000187:drug effects; D002682:Chinchilla; D003630:Daunorubicin; D004562:Electrocardiography / Q000187:drug effects; D018922:HL-60 Cells; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D013318:Stroke Volume / Q000187:drug effects; D020107:Troponin T / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D006835:Hydrazones; D007502:Iron Chelating Agents; D020107:Troponin T; C507461:pyridoxal 2-chlorobenzoyl hydrazone; D011730:Pyridoxal; D003630:Daunorubicin