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: 27.36). 10/2012; 18(11). DOI: 10.1038/nm.2919
Source: PubMed


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
    • "Others pointed to doxorubicin-induced impairment of synthesis of sarcomeric proteins [7] [8] [9] or to cleavage of giant sarcomeric protein titin [10]. Recently, major importance of DNA topoisomerase 2-beta, which is a dominant form in adult cardiomyocytes, has been proposed [11]. Hence, doxorubicin-induced toxicity may represent an interesting cardiomyocyte-specific challenge which can help to understand the functional aspects of H9c2 phenotype. "
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    ABSTRACT: Due to their cardiac origin, H9c2 cells rank among the most popular cell lines in current cardiovascular research, yet molecular phenotype remains elusive. Hence, in this study we used proteomic approach to describe molecular phenotype of H9c2 cells in their undifferentiated (i.e., most frequently used) state, and its functional response to cardiotoxic drug doxorubicin. Of 1671 proteins identified by iTRAQ IEF/LC-MSMS analysis, only 12 proteins were characteristic for striated muscle cells and none was cardiac phenotype-specific. Targeted LC-SRM and western blot analyses confirmed that undifferentiated H9c2 cells are phenotypically considerably different to both primary neonatal cardiomyocytes and adult myocardium. These cells lack proteins essential for formation of striated muscle myofibrils or they express only minor amounts thereof. They also fail to express many proteins important for metabolism of muscle cells. The challenge with clinically relevant concentrations of doxorubicin did not induce a proteomic signature that has been previously noted in primary cardiomyocytes or adult hearts. Instead, several alterations previously described in other cells of mesodermal origin, such as fibroblasts, were observed (e.g., severe down-regulation of collagen synthesis pathway). In conclusion, the molecular phenotype of H9c2 cells resembles very immature myogenic cells with skeletal muscle commitment upon differentiation and thus, translatability of findings obtained in these cells deserves caution.
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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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    • "Indeed, contrary to etoposide and camptothecin , doxorubicin is also a strong DNA intercalator, inducing KAT5-dependent histone acetylation and release from open chromatin (histone eviction) (Choi et al., 2009; Ikura et al., 2000), leading to cell-cycle arrest (Pang et al., 2013). Similarly, DeMAND identified SIK1 as a doxorubicin-specific effector (ranked 36 th ), which is required for cardiac progenitor cell maintenance (CPCs) (Romito et al., 2010), thus pinpointing the compound's key adverse event, i.e., cardiomyopathy followed by congestive heart failure (Zhang et al., 2012b). Both KAT5 and SIK1 were completely missed by t test analysis. "
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    ABSTRACT: Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity. Copyright © 2015 Elsevier Inc. All rights reserved.
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