T h e new england journal o f medicine clinical implications of basic research Anthracyclines and Heart Failure Douglas B. Sawyer, M.D., Ph.D. Since their discovery more than 50 years ago, Anthracyclines are thought to cause cardio- anthracyclines have become the mainstay for the myocyte damage by driving reactions that result treatment of many cancers. However, anthracy- in the formation of free radicals, which in turn clines are associated with a risk of heart failure, can react with and disrupt the function of many with the risk proportionate to the cumulative cellular constituents, causing dysfunction and cell exposure; cardiac injury appears to occur with death. Numerous studies in isolated cells and in every dose, and cardiac-biopsy specimens ob- animals have shown cardioprotective effects of tained within hours after a single dose of an antioxidants, lending support to the hypothesis anthracycline (e.g. doxorubicin or daunorubi- that, as a consequence of anthracycline exposure, cin) show pathologic changes.1 Much effort has reactive oxygen species wreck cardiomyocytes gone into finding ways to prevent anthracycline (Fig. 1). However, clinical trials of antioxidants cardiotoxicity, yet advanced heart failure remains for the prevention of anthracycline-induced car- a consequence of anthracycline exposure. More- diac injury have been disappointing. Nevertheless, over, symptomatic heart failure often occurs dexrazoxane, a compound that chelates iron years after cancer treatment, making it difficult and prevents hydroxyl radical formation in the to evaluate preventive strategies. presence of anthracyclines, prevents cardiac injury, The dominant theory of how anthracyclines lending support to the hypothesis regarding re- cause heart damage involves the generation of active oxygen species. (Dexrazoxane has been ap- reactive oxygen species, which results in damage proved by the Food and Drug Administration for to DNA, proteins, and lipids and leads to cellular the prevention of anthracycline cardiotoxicity.) dysfunction and myocyte death. However, results On the other hand, some research has chal- from a recent study by Zhang et al.2 suggest that lenged the hypothesis regarding reactive oxygen the first step in cardiac myocyte damage from species. Using mouse cells in culture, Lyu et al.3 anthracyclines is independent of reactive oxygen have shown that anthracycline-induced DNA species and depends instead on drug interactions breaks and cell death in a cardiomyocyte cell with a particular type of topoisomerase, an en- line depend on the presence of Top2b. Building zyme that affects the tension and topologic on this finding, Zhang et al. genetically engi- features of DNA. neered mice to lack Top2b specifically in their Anthracyclines disrupt tumor growth by bind- cardiomyocytes. In contrast with control mice, ing to and blocking the function of topoisomer- the mutant mice did not have acute or chronic ase II (TOP2). Topoisomerases break, twist, and cardiac injury after exposure to doxorubicin, a reseal the phosphate backbone of DNA and, in so commonly used anthracycline. Nor did these doing, permit a readjustment in the tension of mice have reductions in left ventricular ejection the double helix during replication and transcrip- fraction, a key characteristic of doxorubicin car- tion. Anthracyclines intercalate into DNA and diotoxicity. form complexes with TOP2 that disrupt the ac- Zhang et al. observed the formation of reac- tivity of the enzyme and activate a DNA-dam- tive oxygen species, consequent to interactions age response, leading to cell death. There are sev- among doxorubicin, Top2b, and DNA in the wild- eral forms of topoisomerase. Rapidly dividing type mice. The formation of reactive oxygen tumor cells express high levels of topoisomerase species appeared to be caused by the disruption II alpha (TOP2A). TOP2 beta (TOP2B) is ubiqui- of mitochondrial function, rather than a conse- tously expressed; cardiomyocytes express TOP2B quence of reduction–oxidation cycling of doxo- but not TOP2A. Anthracyclines target both TOP2A rubicin quinones. Analysis of cardiac tissue from and TOP2B. the doxorubicin-treated wild-type mice revealed 1154 n engl j med 368;12 nejm.org march 21, 2013 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF MICHIGAN on November 4, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. Clinical Implications of Basic Research Anthracycline-Induced Heart Failure: the ROS Hypothesis TOP2B Inhibition as Mechanism for Heart Failure Anthracycline O OH O OH TOP2B alters the tension of DNA during replication and transcription OH by breaking, twisting, and resealing DNA OCH3 O OH O TOP2B R e− Supercoiled ROS · DNA O2 O O2· − H2O2 ·OH Uncoiled double-stranded O− DNA DNA damage Quinone Lipid peroxidation Protein TOP2B carbonylation Anthracyclines intercalate into DNA, forming a complex with TOP2B and thereby inhibiting its enzymatic activity. Anthracyclines DNA double-strand breaks Cellular ↓ PGC1-α and dysfunction and p53 PGC1-β cell death Mitochondrial dysfunction ↓ Mitochondrial Cellular biogenesis ROS dysfunction and cell death Figure 1. Mechanisms of Anthracycline-Induced Injury to Cardiac Cells. The classic model of anthracycline cardiotoxicity involves the generationCOLOR FIGURE of reactive oxygen species (ROS) by the quinone moiety com- mon to all anthracyclines. An alternative model, supported Draftby a4 recent study3/5/2013 by Zhang et al.,2 posits that toxicity is caused by the dis- Author Sawyer_cibr1214975 abling of the function of topoisomerase II beta (TOP2B)Fig #by the1 anthracyclines. Without functional TOP2B, double-stranded DNA breaks accrue, leading to events such as the activation of p53 Titletumor-suppressorAnthracyclines and protein, Heart mitochondrial dysfunction, and the generation of ROS that result in cardiac cell death. PGC1-α and PGC1-β denote peroxisome-proliferator–activatedFailure receptor α coactivator 1α and 1β. DE Phimister ME Laurencot Artist Williams Pub Date 3/21/2013 AUTHOR PLEASE NOTE: the activation of DNA-damage–response path-Figure tanthas been redrawnmice, and type a has finding been reset consistent with the observed ways by means of the suppression of transcrip- protectionPlease check carefully against cardiotoxicity. tion factors known to be critical for regulation of Dexrazoxane was originally developed as a mitochondrial biogenesis (Fig. 1). These changes TOP2 inhibitor. In cells, dexrazoxane appears to were not present in cardiac tissue from the mu- prevent doxorubicin binding to TOP2B and thus n engl j med 368;12 nejm.org march 21, 2013 1155 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF MICHIGAN on November 4, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. Clinical Implications of Basic Research prevents DNA breaks and cell death. An alterna- tively binds to TOP2B could prevent its interac- tive mechanism for the cardioprotective effect of tion with anthracyclines and thus prevent cardiac dexrazoxane may therefore involve prevention cell death. of the binding of anthracyclines to TOP2B, rather Disclosure forms provided by the author are available with the than iron chelation and prevention of damage to full text of this article at NEJM.org. cells from reactive oxygen species. However, the From the Vanderbilt University Medical Center, Nashville. effect of dexrazoxane on TOP2A may reduce the antitumor efficacy of anthracyclines and, 1. Unverferth BJ, Magorien RD, Balcerzak SP, Leier CV, Unver- ironically, limit its usefulness. ferth DV. Early changes in human myocardial nuclei after doxo- rubicin. Cancer 1983;52:215-21. Research is needed to determine whether 2. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the these findings have clinical relevance. In the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med event that they do, the implications of this work 2012;18:1639-42. 3. Lyu YL, Lin C-P, Azarova AM, Cai L, Wang JC, Liu LF. Role of are exciting. The development of inhibitors spe- topoisomerase IIβ in the expression of developmentally regu- cific to TOP2A may lead to efficacious antitumor lated genes. Mol Cell Biol 2006;26:7929-41. therapies that have no effect on the heart. It is DOI: 10.1056/NEJMcibr1214975 also possible that a small molecule that selec- Copyright © 2013 Massachusetts Medical Society. 1156 n engl j med 368;12 nejm.org march 21, 2013 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF MICHIGAN on November 4, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. .