Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Abstract

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 Ϯ 0.5 versus 59.2 Ϯ 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt max ) was significantly higher than in the DAU-only group (1131 Ϯ 125 versus 783 Ϯ 53 kPa/s, p Ͻ 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.

Deferiprone Does Not Protect against Chronic Anthracycline Cardiotoxicity in Vivo

“…Nevertheless, this was well attributable to the hydrophilic nature of this drug, which hinders its penetration into the cardiomyocytes. On the other hand, using our in vivo rabbit model, we have recently shown that lipophilic aryolhydrazone iron chelators are able to protect against anthracycline cardiotoxicity in terms of overall mortality, functional parameters, and histopathology (Simunek et al, 2005a;Sterba et al, 2006Sterba et al, , 2007a. However, at the same time, it was revealed that dexrazoxane is superior to aroylhydrazones, as the cardioprotection of the latter compounds-albeit significant-was always only partial.…”

Ceruloplasmin Protects Injured Spinal Cord from Iron-Mediated Oxidative Damage

“…We used a lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH), an analog of pyridoxal isonicotinoyl hydrazone that shows high affinity and selectivity for iron (Richardson and Ponka, 1998b). These chelators have been used in a number of in vivo and in vitro models, and the dosage we used was based on previous in vivo work (Richardson and Ponka, 1998a;Klimtova et al, 2003;Simunek et al, 2005Simunek et al, , 2008aSterba et al, 2005Sterba et al, , 2006Sterba et al, , 2007. An SIH solution was prepared as reported previously (Klimtova et al, 2003).…”

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

“…SIH and o-108 prevented both premature deaths of animals as well as significantly improved the DAU-induced impairment of cardiac function (LV EF, dP/dt max ), biomarkers of cardiac injury (cTnT), as well as histopathological parameters (255,256). However, dose escalation of all the aroylhydrazone chelators did not provide additional protection, but on the contrary, it hampered virtually all the beneficial effects of the chelators regarding both overall mortality rate and cardioprotection (244,255,256). Importantly, these higher chelators' doses were nontoxic and well tolerated when administered to animals alone.…”

“…as protectors against ANT-induced cardiotoxicity in vitro and/or in vivo (see below), have been also shown not to blunt the antiproliferative effects of ANTs in various cancer cell lines (209,243,256). It should be noted that-with the exception of few DEX analogs (108)-no chelator has been specifically designed for use in prevention of ANT cardiotoxicity.…”

“…This has been observed despite the fact that the studied agents are even stronger and more selective intracellular iron chelators being able to displace iron from its complexes with ANTs, and their own complexes with this metal are less likely to redox cycle than those of ADR-925. Furthermore, in some of those studies, the cardioprotective dose range was quite narrow, and even a slight ( &2.5-fold) dose increase resulted in a disappearance of protective activity (244,255,256,282). It should be noted that while DEX is a prodrug that can be bioactivated to the chelating metabolite ADR-925 at the site of its effect, all the above-listed iron chelators are active ligands from the moment of administration.…”