Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone

Abstract

Background and purpose: The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS). Experimental approach: The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation. Key results: SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU. Conclusions and implications:This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation

“…More recently, the oxidative stress hypothesis has been challenged by the absence of a cardio-protective effect of antioxidant drugs [23] and by the demonstration that the mechanisms of cardioprotection of dexrazoxane and of other iron chelators do not involve a decrease in free radicals formation [24]. Therefore, the contribution of iron to doxorubicin cardiotoxicity does not seem to be totally dependent on free radical formation, and other mechanisms related to anthracycline-induced heart iron accumulation are probably important, especially in the setting of chronic cardiac damage [9].…”

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

“…The observed protection with SIH against both DAU and H 2 O 2 was dependent on iron chelation, as it could be blunted by increasing the concentration of iron salts in the incubation medium. However, while SIH completely abolished the H 2 O 2 -induced significant increase of a lipid peroxidation marker, the protection by SIH against DAU cardiotoxicity was not accompanied by any significant change in this parameter (243).…”

“…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.…”

“…The inability of aroylhydrazone chelators to provide the same degree of protection as DEX could be attributable to their relatively rapid degradation and short plasma half-life, whereas the disappearance of the cardioprotective effect after higher doses might potentially be associated with too high peak plasma concentrations overshooting a desirable degree of iron chelation in ANT-treated cardiomyocytes (140)(141)(142). Therefore, in an attempt to shed light on the results of in vivo experiments, an in vitro study examining protection by SIH against DAU cardiotoxicity and involved mechanisms was conducted, using primary culture of neonatal rat ventricular cardiomyocytes (243). SIH has been shown to protect cardiomyocytes against the 48 h incubation with 10 lM DAU.…”

The iron chelator Dp44mT does not protect myocytes against doxorubicin

“…Iron chelators are also of clinical interest in treating complications of transfusion-dependent b-thalassemia iron overload [2,7]. The structurally related SIH (salicylaldehyde isonicotinoyl hydrazone) has shown some partial daunorubicin cardioprotective activity in vitro [8] and in vivo at lower doses, though not at higher doses [9]. We previously showed that the clinically approved pro-drug iron chelator doxorubicin cardioprotective agent dexrazoxane (ICRF-187, Zinecard TM , Totect TM , Savene TM , Fig.…”