Pyridoxal Isonicotinoyl Hydrazone (PIH) and its Analogs as Protectants Against Anthracycline-Induced Cardiotoxicity

Abstract

The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality.

The iron chelator Dp44mT does not protect myocytes against doxorubicin

“…The ability of other iron chelating drugs, as we and others have shown [47][48][49], have produced mixed results in their ability to reduce anthracycline-induced cardiotoxicity. In the case of our study with ICRF-161, a dexrazoxane analog with three methylene linkers rather than two linkers, we showed that while the ICRF-161 hydrolysis product displaced Fe 3+ from its complex with doxorubicin, it did so much less effectively than for the dexrazoxane hydrolysis product.…”

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.…”

“…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.…”

“…Therefore, iron chelators might also interfere with ANTs and cellular iron in a more complex way than only shielding free iron from being a catalyst in Fenton chemistry. It is possible that an excessive iron binding, such as that apparently induced with ICL670A or Dp44mT treatments (88,89) and too high doses of DFO (282) or aroylhydrazones (244) might exceed the optimal degree of chelation and rather act synergically with the ANT-induced iron metabolism misbalance. Of note, oxidative stress may not be only caused by iron excess, but oxidant-induced damage to mitochondria has been also described from iron deficiency (287).…”