Anthracycline Cardiotoxicity

Abstract

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumours. The first anthracyclines, doxorubicin (DOX) and daunorubicin (DNR), were isolated from Streptomyces var. Peucetius; they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydroquinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH 2 OH in DOX vs-CH 3 in DNR). Second generation anthracyclines, like epirubicin (EPI) and idarubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively. When injected by standard i.v. infusion, anthracyclines show a rapid distribution phase, a high distribution volume at steady state (15 l/kg), a slow elimination phase (successive plasma half-lives of  5 minutes, 1 hour and 30 hours). Anthracyclines are excreted mostly through bile, which imposes special care in patients with hepatic dysfunction (Robert & Gianni, 1993). In comparison with DOX, EPI is characterized by an unique glucuronidation that accelerates its systemic body clearance and imposes administering EPI at doses 1.5 times higher than those of DOX (Innocenti F et al., 2001). Anthracyclines have long been known to kill tumor cells by inhibiting topoisomerase II. Anthracyclines act by stabilizing a reaction intermediate in which DNA strands are cut and covalently linked to topoisomerase II, eventually impeding DNA resealing. Anthracycline intercalation into DNA plays a role in this reaction; in fact, anthracycline rings that do not intercalate into DNA probably stabilize the complex between topoisomerase II and the DNA that it has nicked (Menna et al., 2008). Anthracycline-and topoisomerase II-mediated DNA damage is followed by growth arrest in G1 and G2 and apoptosis. This is usually, but not always, relayed by p53 and the consequent induction of the WAF1/CIP1 p21 gene product, a strong inhibitor of cyclin-dependent kinases that favour cell cycle progression through the G1 to S transition (Minotti et al., 2008). Although topoisomerase II inhibition remains the most persuasive mechanism to explain the antitumor activity of anthracyclines, clinically relevant concentrations of anthracyclines were shown to induce apoptosis through additional mechanisms that were not bound to the topoisomerase II-p53 machinery. These mechanisms include, among others, i) the activation of neutral sphingomyelinases, followed by ceramide formation and converse activation of cell death effectors (c-Jun N-terminal kinase) or down-regulation of survival pathways (Akt/protein kinase B) ii), mitochondrial dysfunction, followed by cytochrome c release and apoptosome formation iii), induction of lipid peroxidation and formation of malondialdehyde-DNA adducts, followed by the reduced activity of cyclin E-and cyclin Bassociated kinase activities and growth arrest in both p53-proficient and p53-deficient cells iv), inhibition of the proteasome, followed by an accumulation of u...

Prevention of doxorubicin-induced cardiomyopathy using targeted MaFGF mediated by nanoparticles combined with ultrasound-targeted MB destruction

“…1 Unfortunately, its clinical application is associated with dose-dependent and essential irreversible cardiotoxicity, which leads to the development of cardiomyopathy and congestive heart failure 2 that is often lethal to the patients. The mechanisms of DOX-induced cardiotoxicity are multifactorial and involve oxidative stress with reactive oxygen species (ROS) generation and cell death through both apoptosis and necrosis.…”

“…3 Cardiac tissues are more vulnerable to oxidative stress caused by DOX-induced cardiotoxicity due to less developed antioxidant defenses, such as SOD1, SOD2, CAT, GSH, and glutathione peroxidase, in the heart compared with other organs, such as the kidney and liver. 1 SOD is an important antioxidant enzyme that protects the cells from damage by scavenging free radicals, so it plays an important role in the balance of oxidation and antioxidation. The generation of ROS attacks the polyunsaturated fatty acids of biofilm and induces lipid peroxidation followed by lipid peroxides such as MDA.…”

Single-Nucleotide Polymorphisms in Aldo-Keto and Carbonyl Reductase Genes Are Not Associated with Acute Cardiotoxicity after Daunorubicin Chemotherapy

“…The large interpatient variability in sensitivity to anthracyclines correlates with the wide range of pharmacokinetic values reported for these drugs, which is largely a reflection of differences in the phase I conversion of anthracyclines to their metabolites catalyzed by the aldo-keto reductases (AKR) and carbonyl reductases (CBR; ref. 1). A cardioprotective role for CBRs has been shown in mouse models (2,3), and it has been proposed that polymorphisms in these genes are likely to affect anthracycline metabolic rates, and thus contribute to anthracycline-induced cardiotoxicity (AIC).…”

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

“…Both the superoxide anion and its dismutation product, hydrogen peroxide, are in fact toxic for the endothelium [57,58]. Endothelial toxicity induced by anthracyclines seems to be influenced by several mechanisms, such as drug accumulation in the nuclei, mitochondria, DNA repair, stressinduced signaling mechanisms, the sarcoplasmic reticulum stress, nitrosative stress, the activity on drug transporters (including MDR1 and MRP1), drug metabolism, and TopI and II inhibition [59,60]. The latter is a cellular target for anthracyclines.…”