Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Nature medicine (Impact Factor: 28.05). 10/2012; 18(11). DOI: 10.1038/nm.2919
Source: PubMed

ABSTRACT Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

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Available from: Sui Zhang, May 14, 2014
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    • "The most adverse effects of DOX for clinical application are bone marrow suppression and cardiotoxicity (Zhang et al., 2012). Doxil Õ or Lipodox Õ was approved by the FDA in 1995 as the first antitumor liposome formulation in which 495% DOX was encapsulated into sterically stabilised liposomes (SSL) that were modified with polyethylene glycol (PEG). "
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    ABSTRACT: Doxorubicin (DOX) is widely used as an antitumor model drug in liposomes because of its high encapsulation efficiency. The cell-penetrating peptide (CPP) has potential applications in drug delivery systems. However, we discovered that the encapsulation efficiency of DOX decreased with increasing modification density of CPP on liposomes. To explore the interaction mechanisms of CPP-modified liposomes (CPPL) for DOX loading, X-ray diffraction, Fourier transform infrared spectroscopy and Raman spectroscopy were utilised, and theoretical calculations based on molecular dynamics simulation were performed. Results showed that the monomeric intermolecular interaction between CPP and DOX, in which the guanidinium group of CPP was parallel to the planar aromatic chromophore of DOX, depending on the cation–pi interaction and hydrogen bonds, weakened the tendency of DOX transporting into the internal medium from the liposomal external medium. Analysis of the interaction between CPP and DOX at the molecular level provided theoretical guidance for the further development of CPPL.
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    • "ion of DOX may affect the heart independently of any interactions with iron . In a recent work performed in mice whose cardiomyocytes were specifically deleted for topoisomerase - IIβ , Zhang et al . suggested that DOX - induced cardiotoxicity was mediated by topoisomerase - IIβ inhibition , which leads to transcriptome changes in cardiomyocytes ( Zhang et al . , 2012 ) . These changes are responsible for defective mitochondrial biogenesis and ROS formation . Additionally , some of the beneficial effects observed with dexrazoxane may be related to its ability to catalytically inhibit topoisomerase II , rather than its iron - chelation activity ( Vavrova et al . , 2013 ) ."
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    ABSTRACT: Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1,000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. Copyright © 2015. Published by Elsevier Inc.
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    • "Moreover, treatment of established adriamycin cardiomyopathy is directly only to HF symptoms. There is no known therapy for reversing the underlying cardiomyopathy [17] [18]. "
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