Myocardial content of selected elements in experimental anthracycline-induced cardiomyopathy in rabbits

Abstract

Cardiotoxicity represents the main drawback of clinical usefulness of anthracycline antineoplastic drugs. In this study, a content of selected elements (Ca, Mg, K, Se, Fe) in the post-mortem removed samples of the myocardial tissue was studied in three groups of rabbits: 1) control group (i.v. saline; n = 10); 2) daunorubicin-receiving animals (DAU; 3 mg/kg, i.v; n = 11); 3) animals receiving cardioprotective iron-chelating agent dexrazoxane (DEX; 60 mg/kg, i.p.; n = 5) prior to DAU. Drugs were administered once weekly for 10 weeks. 5-7 days after the last administration, cardiac left ventricular contractility (dP/dtmax) was significantly decreased in DAU-treated animals (745 +/- 69 versus 1245 +/- 86 kPa/s in the control group; P < 0.05), while in the DEX + DAU group it was insignificantly increased (1411 +/- 77 kPa/s). Of the myocardial elements' content studied, a significant increase in total Ca against control (16.2 +/- 2.4 versus 10.6 +/- 0.9 microg/g of dry tissue; P < 0.05) was determined in the DAU-group, which was accompanied with significant decreases in Mg and K. In the heart tissue of DEX-pretreated animals, no significant changes of elements' content were found as compared to controls, while the Ca content was in these animals significantly lower than in the DAU group (9.1 +/- 0.4 versus 16.2 +/- 2.4 microg/g; P < 0.05). Hence, in this study we show that systolic heart failure induced by chronic DAU administration is primarily accompanied by persistent calcium overload of cardiac tissue and the protective action of DEX is associated with the restoration of normal myocardial Ca content.

Deferiprone Does Not Protect against Chronic Anthracycline Cardiotoxicity in Vivo

“…In addition, anthracyclines and their metabolites have been reported to induce a number of distinct cellular effects, which do not appear to be ROS-mediated (Menna et al, 2007). For example, anthracyclines have been demonstrated to induce a number of perturbations in cellular calcium homeostasis (Simunek et al, 2005b;Wallace, 2007). Unlike in the case of selective iron chelator L1, it can not be excluded that dexrazoxane may also chelate calcium, which can potentially account for the difference in cardioprotective effects of both chelators.…”

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

“…Others have documented that DEX (40 mg/ kg) markedly reduces deleterious effects of DOX (2 mg/kg, weekly for 4 weeks) on trabecular actin-myosin crossbridge cycle (45). DEX (60 mg/kg weekly) was also able to prevent an increase in myocardial total calcium content induced by chronic DAU treatment (3 mg/kg, weekly for 10 weeks) (241). Interestingly, in the latter study, the chronic ANT treatment with or without DEX had no impact on total myocardial iron levels.…”

Alterations in Low-Z Elements Distribution in Heart Tissue after Treatments to Breast Cancer Using LEXRF Technique

“…It seems to be contradictory, based on the fact that lower levels of Mg were associated to cardio toxicity. Nevertheless previous studies about the doxorubicin cardiotoxic effects also reported an increase of Mg levels after chemotherapy administration [41] [42]. Doxorubicin a widely chemo-therapeutic agent, used for BC, and other types of cancer treatment.…”

“…It has been suggested that DOX induces an iron mediated increase in ROS, referred to as the "ROS and iron hypothesis". According to this hypothesis, in the presence of iron, DOX leads to futile redox cycling, inducing substantial ROS production and cellular damage [51] [52] [42]. Ichikawa et al (2014) [53] show that the cardiotoxicity of DOX occurs through preferential accumulation of iron specifically in the mitochondria and that a reversal in mitochondrial iron accumulation alleviates the deleterious effects of DOX on the heart.…”