{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:42:43Z","timestamp":1785213763808,"version":"3.55.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>The cardiovascular toxicity of anticancer drugs promotes the development of cardiovascular diseases. Therefore, cardiovascular toxicity is an important safety issue that must be considered when developing medications and therapeutic applications to treat cancer. Among anticancer drugs, members of the anthracycline family, such as doxorubicin, daunorubicin and mitoxantrone, are known to cause cardiotoxicity and even heart failure. Using human-induced pluripotent stem cell-derived cardiomyocytes in combination with \u201cOmic\u201d technologies, we identified several cardiotoxicity mechanisms and signal transduction pathways. Moreover, these drugs acted as cardiovascular toxicants through a syndrome of mechanisms, including epigenetic ones. Herein, we discuss the main cardiovascular toxicity mechanisms, with an emphasis on those associated with reactive oxygen species and mitochondria that contribute to cardiotoxic epigenetic modifications. We also discuss how to mitigate the cardiotoxic effects of anticancer drugs using available pharmaceutical \u201cweapons.\u201d<\/jats:p>","DOI":"10.3389\/fcvm.2021.658900","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T04:29:41Z","timestamp":1619497781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Epigenetic Mechanisms Involved in the Cardiovascular Toxicity of Anticancer Drugs"],"prefix":"10.3389","volume":"8","author":[{"given":"Panagiota","family":"Papazoglou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luying","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agapios","family":"Sachinidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s10565-006-0140-y","article-title":"Adriamycin-induced oxidative mitochondrial cardiotoxicity","volume":"23","author":"Berthiaume","year":"2007","journal-title":"Cell Biol Toxicol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"7582730","DOI":"10.1155\/2018\/7582730","article-title":"Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib","volume":"2018","author":"Gorini","year":"2018","journal-title":"Oxid Med Cell Longev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.tox.2017.08.011","article-title":"Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity","volume":"390","author":"Ferreira","year":"2017","journal-title":"Toxicology."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1089\/ars.2016.6930","article-title":"From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: a translational overview","volume":"30","author":"Tocchetti","year":"2019","journal-title":"Antioxid Redox Signal."},{"key":"B5","doi-asserted-by":"publisher","first-page":"358","DOI":"10.3390\/ijms21010358","article-title":"Oxidative stress-responsive MicroRNAs in heart injury","volume":"21","author":"Kura","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1521020","DOI":"10.1155\/2017\/1521020","article-title":"Oxidative stress and cellular response to doxorubicin: a common factor in the complex milieu of anthracycline cardiotoxicity","volume":"2017","author":"Cappetta","year":"2017","journal-title":"Oxid Med Cell Longev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"22","DOI":"10.20455\/ros.2016.805","article-title":"Reactive oxygen species","volume":"1","author":"Kasiappan","year":"2016","journal-title":"Cell Med Press."},{"key":"B8","doi-asserted-by":"publisher","first-page":"5381692","DOI":"10.1155\/2019\/5381692","article-title":"Understanding of ROS-inducing strategy in anticancer therapy","volume":"2019","author":"Kim","year":"2019","journal-title":"Oxid Med Cell Longev."},{"key":"B9","doi-asserted-by":"publisher","first-page":"101394","DOI":"10.1016\/j.redox.2019.101394","article-title":"Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: have we been barking up the wrong tree?","volume":"29","author":"Kalyanaraman","year":"2020","journal-title":"Redox Biol."},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1007\/978-981-13-8273-4","volume-title":"Oxidative Stress in Heart Diseases.","author":"Chakraborti","year":"2019"},{"key":"B11","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.critrevonc.2019.03.004","article-title":"Role of epigenetic mechanisms in cisplatin-induced toxicity","volume":"137","author":"Quintanilha","year":"2019","journal-title":"Crit Rev Oncol Hematol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1038\/s41569-020-0348-1","article-title":"Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia","volume":"17","author":"Herrmann","year":"2020","journal-title":"Nat Rev Cardiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"9158572","DOI":"10.1155\/2017\/9158572","article-title":"The management of cardiovascular risk through epigenetic biomarkers","volume":"2017","author":"Metzinger","year":"2017","journal-title":"Biomed Res Int."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.3390\/ijerph15102098","article-title":"Epigenetic effects of drugs of abuse","volume":"15","author":"Heinbockel","year":"2018","journal-title":"Int J Environ Res Public Health."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1177\/1933719117692043","article-title":"HSD11B2, RUNX3, and LINE-1 methylation in placental DNA of hypertensive disorders of pregnancy patients","volume":"24","author":"Majchrzak-Celi\u0144ska","year":"2017","journal-title":"Reprod Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"950","DOI":"10.3389\/fgene.2019.00950","article-title":"Epigenetic biomarkers in cardiovascular diseases","volume":"10","author":"Soler-Botija","year":"2019","journal-title":"Front Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.bbagrm.2011.07.005","article-title":"Assembling chromatin: the long and winding road","volume":"1819","author":"Annunziato","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/hdy.2010.66","article-title":"From genotype to phenotype. What do epigenetics and epigenomics tell us?","volume":"105","author":"Bi\u00e9mont","year":"2010","journal-title":"Heredity."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3425","DOI":"10.3390\/ijms19113425","article-title":"The impact of nutrition and environmental epigenetics on human health and disease","volume":"19","author":"Tiffon","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/s41440-019-0248-0","article-title":"Epigenetic modification: a regulatory mechanism in essential hypertension","volume":"42","author":"Arif","year":"2019","journal-title":"Hypertens Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3389\/fgene.2015.00090","article-title":"DNA methyltransferase 1 mutations and mitochondrial pathology: is mtDNA methylated?","volume":"6","author":"Maresca","year":"2015","journal-title":"Front Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1161\/CIRCRESAHA.115.305206","article-title":"The role of DNA methylation in cardiovascular risk and disease: methodological aspects, study design, and data analysis for epidemiological studies","volume":"118","author":"Zhong","year":"2016","journal-title":"Circ Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1016\/j.jmb.2017.02.008","article-title":"Dynamics and context-dependent roles of DNA methylation","volume":"429","author":"Ambrosi","year":"2017","journal-title":"J Mol Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/1756-8722-6-57","article-title":"Epigenetic changes: a common theme in acute myelogenous leukemogenesis","volume":"6","author":"Gutierrez","year":"2013","journal-title":"J Hematol Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1021\/acs.chemrev.7b00181","article-title":"Lysine acetylation goes global: from epigenetics to metabolism and therapeutics","volume":"118","author":"Ali","year":"2018","journal-title":"Chem Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"4577","DOI":"10.1007\/s00018-015-2023-y","article-title":"Histone methylation modifiers in cellular signaling pathways","volume":"72","author":"Alam","year":"2015","journal-title":"Cell Mol Life Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"9097","DOI":"10.1007\/s11033-020-05916-3","article-title":"Uncovering epigenetic landscape: a new path for biomarkers identification and drug development","volume":"47","author":"De Oliveira","year":"2020","journal-title":"Mol Biol Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/j.tcb.2019.05.004","article-title":"The complexity of PRC2 subcomplexes","volume":"29","author":"Van Mierlo","year":"2019","journal-title":"Trends Cell Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.jacc.2017.05.067","article-title":"Translational perspective on epigenetics in cardiovascular disease","volume":"70","author":"Van Der Harst","year":"2017","journal-title":"J Am Coll Cardiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.tips.2020.01.005","article-title":"Epimimetics: novel therapeutics targeting epigenetic mediators and modulators","volume":"41","author":"Hannan","year":"2020","journal-title":"Trends Pharmacol Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cbpa.2019.01.024","article-title":"The roles of microRNAs in epigenetic regulation","volume":"51","author":"Yao","year":"2019","journal-title":"Curr Opin Chem Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nrd.2016.246","article-title":"MicroRNA therapeutics: towards a new era for the management of cancer and other diseases","volume":"16","author":"Rupaimoole","year":"2017","journal-title":"Nat Rev Drug Discov."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e0180571","DOI":"10.1371\/journal.pone.0180571","article-title":"Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy","volume":"12","author":"Piotrowska","year":"2017","journal-title":"PLoS ONE."},{"key":"B34","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1093\/toxsci\/kfx150","article-title":"Editor's highlight: the altered DNA methylome of chronic doxorubicin exposure in sprague dawley rats","volume":"159","author":"Nordgren","year":"2017","journal-title":"Toxicol Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s00204-019-02626-z","article-title":"Doxorubicin persistently rewires cardiac circadian homeostasis in mice","volume":"94","author":"Ferreira","year":"2020","journal-title":"Arch Toxicol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1111\/bph.13792","article-title":"The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system","volume":"174","author":"Kietzmann","year":"2017","journal-title":"Br J Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"4278658","DOI":"10.1155\/2019\/4278658","article-title":"Reactive oxygen species drive epigenetic changes in radiation-induced fibrosis","volume":"2019","author":"Shrishrimal","year":"2019","journal-title":"Oxid Med Cell Longev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s11739-018-1853-7","article-title":"ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations-authors' reply","volume":"13","author":"Raschi","year":"2018","journal-title":"Intern Emerg Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/978-94-007-4525-4_5","article-title":"Metabolic aspects of epigenome: coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module","volume":"61","author":"Igarashi","year":"2013","journal-title":"Subcell Biochem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.tem.2019.11.009","article-title":"Metabolism, epigenetics, and causal inference in heart failure","volume":"31","author":"Kimball","year":"2020","journal-title":"Trends Endocrinol Metab."},{"key":"B41","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3389\/fcvm.2020.00056","article-title":"Review on the role of epigenetic modifications in doxorubicin-induced cardiotoxicity","volume":"7","author":"Kumari","year":"2020","journal-title":"Front Cardiovasc Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1161\/CIRCRESAHA.119.314681","article-title":"Mitochondrial determinants of doxorubicin-induced cardiomyopathy","volume":"126","author":"Wallace","year":"2020","journal-title":"Circ Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1007\/s00204-018-2170-7","article-title":"Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells","volume":"92","author":"Nemade","year":"2018","journal-title":"Arch Toxicol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"554","DOI":"10.3390\/cells9030554","article-title":"Cyclooxygenases inhibitors efficiently induce cardiomyogenesis in human pluripotent stem cells","volume":"9","author":"Nemade","year":"2020","journal-title":"Cells."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1007\/s00204-015-1623-5","article-title":"Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment","volume":"90","author":"Chaudhari","year":"2016","journal-title":"Arch Toxicol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s00204-017-2065-z","article-title":"Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes","volume":"92","author":"Chaudhari","year":"2018","journal-title":"Arch Toxicol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"5335","DOI":"10.3390\/ijms20215335","article-title":"The yin-yang regulation of reactive oxygen species and MicroRNAs in cancer","volume":"20","author":"Babu","year":"2019","journal-title":"Int J Mol Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2415324","DOI":"10.1155\/2020\/2415324","article-title":"Crosstalk of MicroRNAs and oxidative stress in the pathogenesis of cancer","volume":"2020","author":"Lu","year":"2020","journal-title":"Oxid Med Cell Longev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.7150\/ijms.41980","article-title":"Inhibition of miR-25 attenuates doxorubicin-induced apoptosis, reactive oxygen species production and DNA damage by targeting PTEN","volume":"17","author":"Li","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s10741-017-9653-0","article-title":"Role of microRNAs in doxorubicin-induced cardiotoxicity: an overview of preclinical models and cancer patients","volume":"23","author":"Ruggeri","year":"2018","journal-title":"Heart Fail Rev."},{"key":"B51","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.molmed.2019.04.003","article-title":"Road map for development of stem cell-based alternative test methods","volume":"25","author":"Sachinidis","year":"2019","journal-title":"Trends Mol Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3087","DOI":"10.1007\/s00204-016-1668-0","article-title":"MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes","volume":"90","author":"Chaudhari","year":"2016","journal-title":"Arch Toxicol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.3390\/cells9041001","article-title":"Cardiotoxicity and heart failure: lessons from human-induced pluripotent stem cell-derived cardiomyocytes and anticancer drugs","volume":"9","author":"Sachinidis","year":"2020","journal-title":"Cells."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1007\/s00726-017-2419-0","article-title":"Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes","volume":"49","author":"Chaudhari","year":"2017","journal-title":"Amino Acids."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1016\/j.bbadis.2016.12.021","article-title":"Rutin attenuates doxorubicin-induced cardiotoxicity via regulating autophagy and apoptosis","volume":"1863","author":"Ma","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"B56","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3389\/fphys.2015.00033","article-title":"Carbon monoxide and mitochondria\u2014modulation of cell metabolism, redox response and cell death","volume":"6","author":"Almeida","year":"2015","journal-title":"Front Physiol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2324","DOI":"10.1111\/jcmm.12633","article-title":"Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity","volume":"19","author":"Gu","year":"2015","journal-title":"J Cell Mol Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3390\/ijms20071616","article-title":"Mechanism of action for HDAC inhibitors-insights from omics approaches","author":"Li","year":"2019","journal-title":"Int J Mol Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/ejhf.1439","article-title":"The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity","volume":"21","author":"Russo","year":"2019","journal-title":"Eur J Heart Fail."},{"key":"B60","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1007\/s10741-019-09820-2","article-title":"Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens","volume":"24","author":"Cadeddu Dessalvi","year":"2019","journal-title":"Heart Fail Rev."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.658900\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T04:29:45Z","timestamp":1619497785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.658900\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":60,"alternative-id":["10.3389\/fcvm.2021.658900"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.658900","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,27]]},"article-number":"658900"}}