{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:25:45Z","timestamp":1787829945532,"version":"build-2784847793"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:00:00Z","timestamp":1584403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003406","name":"Tekes","doi-asserted-by":"publisher","award":["40395\/13"],"award-info":[{"award-number":["40395\/13"]}],"id":[{"id":"10.13039\/501100003406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005878","name":"Terveyden Tutkimuksen Toimikunta","doi-asserted-by":"publisher","award":["2666621"],"award-info":[{"award-number":["2666621"]}],"id":[{"id":"10.13039\/501100005878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005633","name":"Syd\u00e4ntutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1\u20133\u00a0\u00b5M markedly reduced (60%) hiPSC-CM viability already within 48\u00a0h, while a 14-day treatment with 100\u00a0nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3\/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2\u00a0weeks (30\u00a0mg\/kg\/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity.<\/jats:p>","DOI":"10.1007\/s00204-020-02711-8","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T19:59:24Z","timestamp":1584475164000},"page":"2113-2130","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes"],"prefix":"10.1007","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8172-485X","authenticated-orcid":false,"given":"S. Tuuli","family":"Karhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-8306","authenticated-orcid":false,"given":"Sini M.","family":"Kinnunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja","family":"T\u00f6lli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9687-8197","authenticated-orcid":false,"given":"Mika J.","family":"V\u00e4lim\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-6505","authenticated-orcid":false,"given":"Virpi","family":"Talman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8971-1359","authenticated-orcid":false,"given":"Heikki","family":"Ruskoaho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,17]]},"reference":[{"key":"2711_CR1","doi-asserted-by":"publisher","first-page":"6975","DOI":"10.1073\/pnas.0401833101","volume":"101","author":"A Aries","year":"2004","unstructured":"Aries A, Paradis P, Lefebvre C, Schwartz RJ, Nemer M (2004) Essential role of GATA4 in cell survival and drug-induced cardiotoxicity. Proc Natl Acad Sci USA 101:6975\u20136980. https:\/\/doi.org\/10.1073\/pnas.0401833101","journal-title":"Proc Natl Acad Sci USA"},{"key":"2711_CR2","doi-asserted-by":"publisher","first-page":"e1566","DOI":"10.1038\/cddis.2014.524","volume":"5","author":"A Aries","year":"2014","unstructured":"Aries A, Whitcomb J, Shao W, Komati H, Saleh M, Nemer M (2014) Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate. Cell Death Dis 5:e1566. https:\/\/doi.org\/10.1038\/cddis.2014.524","journal-title":"Cell Death Dis"},{"key":"2711_CR3","first-page":"1789","volume":"60","author":"OJ Arola","year":"2000","unstructured":"Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio-Pulkki LM (2000) Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60:1789\u20131792","journal-title":"Cancer Res"},{"key":"2711_CR4","doi-asserted-by":"publisher","first-page":"684-017-3677-7","DOI":"10.1073\/pnas.0401833101","volume":"17","author":"WJ Aston","year":"2017","unstructured":"Aston WJ, Hope DE, Nowak AK, Robinson BW, Lake RA, Lesterhuis WJ (2017) A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice. BMC Cancer 17:684-017-3677-7. https:\/\/doi.org\/10.1073\/pnas.0401833101","journal-title":"BMC Cancer"},{"key":"2711_CR5","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.ejps.2010.07.015","volume":"41","author":"DR Barpe","year":"2010","unstructured":"Barpe DR, Rosa DD, Froehlich PE (2010) Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass. Eur J Pharm Sci 41:458\u2013463. https:\/\/doi.org\/10.1016\/j.ejps.2010.07.015","journal-title":"Eur J Pharm Sci"},{"key":"2711_CR81","doi-asserted-by":"publisher","first-page":"10428","DOI":"10.1158\/0008-5472.CAN-07-1344","volume":"67","author":"S Bien","year":"2007","unstructured":"Bien S, Riad A, Ritter CA, Gratz M, Olshausen F, Westermann D, Grube M, Krieg T, Ciecholewski S, Felix SB, Staudt A, Schultheiss HP, Ewert R, Volker U, Tschope C, Kroemer HK (2007) The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res 67:10428\u201310435. https:\/\/doi.org\/10.1158\/0008-5472.CAN-07-1344","journal-title":"Cancer Res"},{"key":"2711_CR7","doi-asserted-by":"publisher","first-page":"14471","DOI":"10.1073\/pnas.0602543103","volume":"103","author":"E Bisping","year":"2006","unstructured":"Bisping E, Ikeda S, Kong SW, Tarnavski O, Bodyak N, McMullen JR, Rajagopal S, Son JK, Ma Q, Springer Z, Kang PM, Izumo S, Pu WT (2006) GATA4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc Natl Acad Sci USA 103:14471\u201314476. https:\/\/doi.org\/10.1073\/pnas.0602543103","journal-title":"Proc Natl Acad Sci USA"},{"key":"2711_CR8","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.ijcard.2007.10.058","volume":"131","author":"V Bistola","year":"2008","unstructured":"Bistola V, Nikolopoulou M, Derventzi A, Kataki A, Sfyras N, Nikou N, Toutouza M, Toutouzas P, Stefanadis C, Konstadoulakis MM (2008) Long-term primary cultures of human adult atrial cardiac myocytes: cell viability, structural properties and BNP secretion in vitro. Int J Cardiol 131:113\u2013122. https:\/\/doi.org\/10.1016\/j.ijcard.2007.10.058","journal-title":"Int J Cardiol"},{"key":"2711_CR9","doi-asserted-by":"publisher","first-page":"H2678","DOI":"10.1152\/ajpheart.1997.273.6.H2678","volume":"273","author":"BG Bruneau","year":"1997","unstructured":"Bruneau BG, Piazza LA, de Bold AJ (1997) BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria. Am J Physiol 273:H2678\u2013H2686. https:\/\/doi.org\/10.1152\/ajpheart.1997.273.6.H2678","journal-title":"Am J Physiol"},{"key":"2711_CR10","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/nmeth.2999","volume":"11","author":"PW Burridge","year":"2014","unstructured":"Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, Lan F, Diecke S, Huber B, Mordwinkin NM, Plews JR, Abilez OJ, Cui B, Gold JD, Wu JC (2014) Chemically defined generation of human cardiomyocytes. Nat Methods 11:855\u2013860. https:\/\/doi.org\/10.1038\/nmeth.2999","journal-title":"Nat Methods"},{"key":"2711_CR11","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nm.4087","volume":"22","author":"PW Burridge","year":"2016","unstructured":"Burridge PW, Li YF, Matsa E, Wu H, Ong SG, Sharma A, Holmstrom A, Chang AC, Coronado MJ, Ebert AD, Knowles JW, Telli ML, Witteles RM, Blau HM, Bernstein D, Altman RB, Wu JC (2016) Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med 22:547\u2013556. https:\/\/doi.org\/10.1038\/nm.4087","journal-title":"Nat Med"},{"key":"2711_CR12","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1089\/dna.1983.2.329","volume":"2","author":"G Cathala","year":"1983","unstructured":"Cathala G, Savouret JF, Mendez B, West BL, Karin M, Martial JA, Baxter JD (1983) A method for isolation of intact, translationally active ribonucleic acid. DNA 2:329\u2013335. https:\/\/doi.org\/10.1089\/dna.1983.2.329","journal-title":"DNA"},{"key":"2711_CR13","doi-asserted-by":"publisher","first-page":"2702","DOI":"10.1101\/gad.915701","volume":"15","author":"F Charron","year":"2001","unstructured":"Charron F, Tsimiklis G, Arcand M, Robitaille L, Liang Q, Molkentin JD, Meloche S, Nemer M (2001) Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev 15:2702\u20132719. https:\/\/doi.org\/10.1101\/gad.915701","journal-title":"Genes Dev"},{"key":"2711_CR14","doi-asserted-by":"publisher","first-page":"3087","DOI":"10.1007\/s00204-016-1668-0","volume":"90","author":"U Chaudhari","year":"2016","unstructured":"Chaudhari U, Nemade H, Gaspar JA, Hescheler J, Hengstler JG, Sachinidis A (2016a) MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol 90:3087\u20133098. https:\/\/doi.org\/10.1007\/s00204-016-1668-0","journal-title":"Arch Toxicol"},{"key":"2711_CR15","doi-asserted-by":"publisher","first-page":"2763","DOI":"10.1007\/s00204-015-1623-5","volume":"90","author":"U Chaudhari","year":"2016","unstructured":"Chaudhari U, Nemade H, Wagh V, Gaspar JA, Ellis JK, Srinivasan SP, Spitkovski D, Nguemo F, Louisse J, Bremer S, Hescheler J, Keun HC, Hengstler JG, Sachinidis A (2016b) Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol 90:2763\u20132777. https:\/\/doi.org\/10.1007\/s00204-015-1623-5","journal-title":"Arch Toxicol"},{"key":"2711_CR16","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1186\/s12885-015-1407-6","volume":"15","author":"A Conway","year":"2015","unstructured":"Conway A, McCarthy AL, Lawrence P, Clark RA (2015) The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review. BMC Cancer 15:366. https:\/\/doi.org\/10.1186\/s12885-015-1407-6","journal-title":"BMC Cancer"},{"key":"2711_CR17","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1111\/1440-1681.13036","volume":"46","author":"R Corremans","year":"2019","unstructured":"Corremans R, Adao R, De Keulenaer GW, Leite-Moreira AF, Bras-Silva C (2019) Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity. Clin Exp Pharmacol Physiol 46:204\u2013215. https:\/\/doi.org\/10.1111\/1440-1681.13036","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"2711_CR18","first-page":"216","volume":"36","author":"WA Creasey","year":"1976","unstructured":"Creasey WA, McIntosh LS, Brescia T, Odujinrin O, Aspnes GT, Murray E, Marsh JC (1976) Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res 36:216\u2013221","journal-title":"Cancer Res"},{"key":"2711_CR19","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/978-1-4419-6199-0_9","volume":"676","author":"Z Darzynkiewicz","year":"2010","unstructured":"Darzynkiewicz Z, Halicka HD, Zhao H (2010) Analysis of cellular DNA content by flow and laser scanning cytometry. Adv Exp Med Biol 676:137\u2013147. https:\/\/doi.org\/10.1007\/978-1-4419-6199-0_9","journal-title":"Adv Exp Med Biol"},{"key":"2711_CR43","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/S0140-6736(03)13976-1","volume":"362","author":"JA de Lemos","year":"2003","unstructured":"de Lemos JA, McGuire DK, Drazner MH (2003) B-type natriuretic peptide in cardiovascular disease. Lancet 362:316\u2013322. https:\/\/doi.org\/10.1016\/S0140-6736(03)13976-1","journal-title":"Lancet"},{"key":"2711_CR20","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1002\/cyto.a.22333","volume":"83","author":"QW Doan-Xuan","year":"2013","unstructured":"Doan-Xuan QW, Sarvari AK, Fischer-Posovsky P, Wabitsch M, Balajthy Z, Fesus L, Bacso Z (2013) High content analysis of differentiation and cell death in human adipocytes. Cytom Part A 83:933\u2013943. https:\/\/doi.org\/10.1002\/cyto.a.22333","journal-title":"Cytom Part A"},{"key":"2711_CR21","doi-asserted-by":"publisher","first-page":"H1048","DOI":"10.1152\/ajpheart.01102.2007","volume":"294","author":"M Esaki","year":"2008","unstructured":"Esaki M, Takemura G, Kosai K, Takahashi T, Miyata S, Li L, Goto K, Maruyama R, Okada H, Kanamori H, Ogino A, Ushikoshi H, Minatoguchi S, Fujiwara T, Fujiwara H (2008) Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294:H1048\u2013H1057. https:\/\/doi.org\/10.1152\/ajpheart.01102.2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2711_CR22","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201701276","author":"MPA Ferreira","year":"2017","unstructured":"Ferreira MPA, Ranjan S, Kinnunen S, Correia A, Talman V, Makila E, Barrios-Lopez B, Kemell M, Balasubramanian V, Salonen J, Hirvonen J, Ruskoaho H, Airaksinen AJ, Santos HA (2017) Drug-loaded multifunctional nanoparticles targeted to the endocardial layer of the injured heart modulate hypertrophic signaling. Small. https:\/\/doi.org\/10.1002\/smll.201701276","journal-title":"Small"},{"key":"2711_CR23","doi-asserted-by":"publisher","first-page":"3777","DOI":"10.1200\/JCO.2007.14.9401","volume":"26","author":"L Gianni","year":"2008","unstructured":"Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB (2008) Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 26:3777\u20133784. https:\/\/doi.org\/10.1200\/JCO.2007.14.9401","journal-title":"J Clin Oncol"},{"key":"2711_CR24","first-page":"3417","volume":"43","author":"RF Greene","year":"1983","unstructured":"Greene RF, Collins JM, Jenkins JF, Speyer JL, Myers CE (1983) Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Cancer Res 43:3417\u20133421","journal-title":"Cancer Res"},{"key":"2711_CR25","doi-asserted-by":"publisher","first-page":"3943","DOI":"10.1161\/01.cir.96.11.3943","volume":"96","author":"K Hasegawa","year":"1997","unstructured":"Hasegawa K, Lee SJ, Jobe SM, Markham BE, Kitsis RN (1997) cis-Acting sequences that mediate induction of \u03b2-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation 96:3943\u20133953. https:\/\/doi.org\/10.1161\/01.cir.96.11.3943","journal-title":"Circulation"},{"key":"2711_CR26","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1161\/01.cir.103.5.730","volume":"103","author":"N Hautala","year":"2001","unstructured":"Hautala N, Tokola H, Luodonpaa M, Puhakka J, Romppanen H, Vuolteenaho O, Ruskoaho H (2001) Pressure overload increases GATA4 binding activity via endothelin-1. Circulation 103:730\u2013735. https:\/\/doi.org\/10.1161\/01.cir.103.5.730","journal-title":"Circulation"},{"key":"2711_CR27","first-page":"20","volume":"46","author":"R Hayward","year":"2007","unstructured":"Hayward R, Hydock DS (2007) Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci 46:20\u201332","journal-title":"J Am Assoc Lab Anim Sci"},{"key":"2711_CR28","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/bf00434396","volume":"5","author":"PB Johansen","year":"1981","unstructured":"Johansen PB (1981) Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother Pharmacol 5:267\u2013270. https:\/\/doi.org\/10.1007\/bf00434396","journal-title":"Cancer Chemother Pharmacol"},{"key":"2711_CR29","doi-asserted-by":"publisher","first-page":"8284","DOI":"10.1021\/acs.jmedchem.9b01086","volume":"62","author":"M Jumppanen","year":"2019","unstructured":"Jumppanen M, Kinnunen SM, V\u00e4lim\u00e4ki MJ, Talman V, Auno S, Bruun T, Boije Af Genn\u00e4s G, Xhaard H, Aumuller IB, Ruskoaho H, Yli-Kauhaluoma J (2019) Synthesis, identification, and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators. J Med Chem 62:8284\u20138310. https:\/\/doi.org\/10.1021\/acs.jmedchem.9b01086","journal-title":"J Med Chem"},{"key":"2711_CR30","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s00441-016-2527-2","volume":"367","author":"A Jurado Acosta","year":"2017","unstructured":"Jurado Acosta A, Rys\u00e4 J, Szabo Z, Moilanen AM, Komati H, Nemer M, Ruskoaho H (2017) Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression. Cell Tissue Res 367:369\u2013385. https:\/\/doi.org\/10.1007\/s00441-016-2527-2","journal-title":"Cell Tissue Res"},{"key":"2711_CR31","doi-asserted-by":"publisher","first-page":"220","DOI":"10.3109\/10520299509108199","volume":"70","author":"J Kapuscinski","year":"1995","unstructured":"Kapuscinski J (1995) DAPI: a DNA-specific fluorescent probe. Biotech Histochem 70:220\u2013233","journal-title":"Biotech Histochem"},{"key":"2711_CR32","doi-asserted-by":"publisher","first-page":"2897","DOI":"10.1007\/s00204-018-2257-1","volume":"92","author":"ST Karhu","year":"2018","unstructured":"Karhu ST, V\u00e4lim\u00e4ki MJ, Jumppanen M, Kinnunen SM, Pohjolainen L, Leigh RS, Auno S, Foldes G, Boije Af Genn\u00e4s G, Yli-Kauhaluoma J, Ruskoaho H, Talman V (2018) Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds. Arch Toxicol 92:2897\u20132911. https:\/\/doi.org\/10.1007\/s00204-018-2257-1","journal-title":"Arch Toxicol"},{"key":"2711_CR33","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1002\/(SICI)1097-0142(19970115)79:2%3c214::AID-CNCR3%3e3.0.CO;2-K","volume":"79","author":"H Kawai","year":"1997","unstructured":"Kawai H, Minamiya Y, Kitamura M, Matsuzaki I, Hashimoto M, Suzuki H, Abo S (1997) Direct measurement of doxorubicin concentration in the intact, living single cancer cell during hyperthermia. Cancer 79:214\u2013219. https:\/\/doi.org\/10.1002\/(SICI)1097-0142(19970115)79:2%3c214:AID-CNCR3%3e3.0.CO;2-K","journal-title":"Cancer"},{"key":"2711_CR34","doi-asserted-by":"publisher","first-page":"13752","DOI":"10.1074\/jbc.M105736200","volume":"277","author":"R Kerkel\u00e4","year":"2002","unstructured":"Kerkel\u00e4 R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H (2002) Distinct roles of mitogen-activated protein kinase pathways in GATA4 transcription factor-mediated regulation of B-type natriuretic peptide gene. J Biol Chem 277:13752\u201313760. https:\/\/doi.org\/10.1074\/jbc.M105736200","journal-title":"J Biol Chem"},{"key":"2711_CR35","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1124\/mol.63.2.368","volume":"63","author":"Y Kim","year":"2003","unstructured":"Kim Y, Ma AG, Kitta K, Fitch SN, Ikeda T, Ihara Y, Simon AR, Evans T, Suzuki YJ (2003) Anthracycline-induced suppression of GATA4 transcription factor: implication in the regulation of cardiac myocyte apoptosis. Mol Pharmacol 63:368\u2013377. https:\/\/doi.org\/10.1124\/mol.63.2.368","journal-title":"Mol Pharmacol"},{"key":"2711_CR36","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1161\/01.res.70.6.1244","volume":"70","author":"P Kinnunen","year":"1992","unstructured":"Kinnunen P, Vuolteenaho O, Uusimaa P, Ruskoaho H (1992) Passive mechanical stretch releases atrial natriuretic peptide from rat ventricular myocardium. Circ Res 70:1244\u20131253. https:\/\/doi.org\/10.1161\/01.res.70.6.1244","journal-title":"Circ Res"},{"key":"2711_CR37","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1210\/endo.132.5.8477647","volume":"132","author":"P Kinnunen","year":"1993","unstructured":"Kinnunen P, Vuolteenaho O, Ruskoaho H (1993) Mechanisms of atrial and brain natriuretic peptide release from rat ventricular myocardium: effect of stretching. Endocrinology 132:1961\u20131970. https:\/\/doi.org\/10.1210\/endo.132.5.8477647","journal-title":"Endocrinology"},{"key":"2711_CR38","doi-asserted-by":"publisher","first-page":"4611","DOI":"10.1038\/s41598-018-22830-8","volume":"8","author":"SM Kinnunen","year":"2018","unstructured":"Kinnunen SM, T\u00f6lli M, V\u00e4lim\u00e4ki MJ, Gao E, Szabo Z, Rys\u00e4 J, Ferreira MPA, Ohukainen P, Serpi R, Correia A, M\u00e4kil\u00e4 E, Salonen J, Hirvonen J, Santos HA, Ruskoaho H (2018) Cardiac actions of a small molecule inhibitor targeting GATA4-NKX2-5 interaction. Sci Rep 8:4611. https:\/\/doi.org\/10.1038\/s41598-018-22830-8","journal-title":"Sci Rep"},{"key":"2711_CR39","doi-asserted-by":"publisher","first-page":"4705","DOI":"10.1074\/jbc.M211616200","volume":"278","author":"K Kitta","year":"2003","unstructured":"Kitta K, Day RM, Kim Y, Torregroza I, Evans T, Suzuki YJ (2003) Hepatocyte growth factor induces GATA4 phosphorylation and cell survival in cardiac muscle cells. J Biol Chem 278:4705\u20134712. https:\/\/doi.org\/10.1074\/jbc.M211616200","journal-title":"J Biol Chem"},{"key":"2711_CR40","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1096\/fj.05-5426fje","volume":"20","author":"S Kobayashi","year":"2006","unstructured":"Kobayashi S, Lackey T, Huang Y, Bisping E, Pu WT, Boxer LM, Liang Q (2006) Transcription factor GATA4 regulates cardiac BCL2 gene expression in vitro and in vivo. FASEB J 20:800\u2013802. https:\/\/doi.org\/10.1096\/fj.05-5426fje","journal-title":"FASEB J"},{"key":"2711_CR41","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1074\/jbc.M109.070037","volume":"285","author":"S Kobayashi","year":"2010","unstructured":"Kobayashi S, Volden P, Timm D, Mao K, Xu X, Liang Q (2010) Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem 285:793\u2013804. https:\/\/doi.org\/10.1074\/jbc.M109.070037","journal-title":"J Biol Chem"},{"key":"2711_CR42","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1124\/jpet.110.170191","volume":"334","author":"S Koka","year":"2010","unstructured":"Koka S, Das A, Zhu SG, Durrant D, Xi L, Kukreja RC (2010) Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther 334:1023\u20131030. https:\/\/doi.org\/10.1124\/jpet.110.170191","journal-title":"J Pharmacol Exp Ther"},{"key":"2711_CR44","doi-asserted-by":"publisher","first-page":"30245","DOI":"10.1074\/jbc.M102174200","volume":"276","author":"Q Liang","year":"2001","unstructured":"Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE, Molkentin JD (2001) The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem 276:30245\u201330253. https:\/\/doi.org\/10.1074\/jbc.M102174200","journal-title":"J Biol Chem"},{"key":"2711_CR45","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.tiv.2017.04.023","volume":"42","author":"J Louisse","year":"2017","unstructured":"Louisse J, Wust RCI, Pistollato F, Palosaari T, Barilari M, Macko P, Bremer S, Prieto P (2017) Assessment of acute and chronic toxicity of doxorubicin in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol In Vitro 42:182\u2013190. https:\/\/doi.org\/10.1016\/j.tiv.2017.04.023","journal-title":"Toxicol In Vitro"},{"key":"2711_CR46","doi-asserted-by":"publisher","first-page":"8839","DOI":"10.1158\/0008-5472.CAN-07-1649","volume":"67","author":"YL Lyu","year":"2007","unstructured":"Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF (2007) Topoisomerase II beta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 67:8839\u20138846. https:\/\/doi.org\/10.1158\/0008-5472.CAN-07-1649","journal-title":"Cancer Res"},{"key":"2711_CR47","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.yjmcc.2004.01.001","volume":"36","author":"KK Ma","year":"2004","unstructured":"Ma KK, Ogawa T, de Bold AJ (2004) Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase. J Mol Cell Cardiol 36:505\u2013513. https:\/\/doi.org\/10.1016\/j.yjmcc.2004.01.001","journal-title":"J Mol Cell Cardiol"},{"key":"2711_CR48","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1007\/s10741-015-9497-4","volume":"20","author":"R Madonna","year":"2015","unstructured":"Madonna R, Cadeddu C, Deidda M, Mele D, Monte I, Novo G, Pagliaro P, Pepe A, Spallarossa P, Tocchetti CG, Zito C, Mercuro G (2015) Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection. Heart Fail Rev 20:621\u2013631. https:\/\/doi.org\/10.1007\/s10741-015-9497-4","journal-title":"Heart Fail Rev"},{"key":"2711_CR49","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1474-9726.2007.00358.x","volume":"7","author":"Y Maejima","year":"2008","unstructured":"Maejima Y, Adachi S, Ito H, Hirao K, Isobe M (2008) Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell 7:125\u2013136. https:\/\/doi.org\/10.1111\/j.1474-9726.2007.00358.x","journal-title":"Aging Cell"},{"key":"2711_CR50","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.mce.2007.05.003","volume":"273","author":"T Majalahti","year":"2007","unstructured":"Majalahti T, Suo-Palosaari M, Sarman B, Hautala N, Pikkarainen S, Tokola H, Vuolteenaho O, Wang J, Paradis P, Nemer M, Ruskoaho H (2007) Cardiac BNP gene activation by angiotensin II in vivo. Mol Cell Endocrinol 273:59\u201367. https:\/\/doi.org\/10.1016\/j.mce.2007.05.003","journal-title":"Mol Cell Endocrinol"},{"key":"2711_CR51","doi-asserted-by":"publisher","first-page":"13721","DOI":"10.1074\/jbc.275.18.13721","volume":"275","author":"T Morimoto","year":"2000","unstructured":"Morimoto T, Hasegawa K, Kaburagi S, Kakita T, Wada H, Yanazume T, Sasayama S (2000) Phosphorylation of GATA4 is involved in alpha 1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem 275:13721\u201313726. https:\/\/doi.org\/10.1074\/jbc.275.18.13721","journal-title":"J Biol Chem"},{"key":"2711_CR52","doi-asserted-by":"publisher","first-page":"28586","DOI":"10.1074\/jbc.M103166200","volume":"276","author":"C Morisco","year":"2001","unstructured":"Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J (2001) Glycogen synthase kinase 3\u03b2 regulates GATA4 in cardiac myocytes. J Biol Chem 276:28586\u201328597. https:\/\/doi.org\/10.1074\/jbc.M103166200","journal-title":"J Biol Chem"},{"key":"2711_CR53","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","volume":"65","author":"T Mosmann","year":"1983","unstructured":"Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55\u201363. https:\/\/doi.org\/10.1016\/0022-1759(83)90303-4","journal-title":"J Immunol Methods"},{"key":"2711_CR54","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/bf00735923","volume":"32","author":"C Muller","year":"1993","unstructured":"Muller C, Chatelut E, Gualano V, De Forni M, Huguet F, Attal M, Canal P, Laurent G (1993) Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion. Cancer Chemother Pharmacol 32:379\u2013384. https:\/\/doi.org\/10.1007\/bf00735923","journal-title":"Cancer Chemother Pharmacol"},{"key":"2711_CR55","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/j.yjmcc.2012.03.006","volume":"52","author":"Y Octavia","year":"2012","unstructured":"Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52:1213\u20131225. https:\/\/doi.org\/10.1016\/j.yjmcc.2012.03.006","journal-title":"J Mol Cell Cardiol"},{"key":"2711_CR56","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1161\/01.res.69.2.491","volume":"69","author":"Y Ogawa","year":"1991","unstructured":"Ogawa Y, Nakao K, Mukoyama M, Hosoda K, Shirakami G, Arai H, Saito Y, Suga S, Jougasaki M, Imura H (1991) Natriuretic peptides as cardiac hormones in normotensive and spontaneously hypertensive rats. The ventricle is a major site of synthesis and secretion of brain natriuretic peptide. Circ Res 69:491\u2013500. https:\/\/doi.org\/10.1161\/01.res.69.2.491","journal-title":"Circ Res"},{"key":"2711_CR57","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1161\/01.RES.0000215985.18538.c4","volume":"98","author":"T Oka","year":"2006","unstructured":"Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, Duncan SA, Molkentin JD (2006) Cardiac-specific deletion of GATA4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res 98:837\u2013845. https:\/\/doi.org\/10.1161\/01.RES.0000215985.18538.c4","journal-title":"Circ Res"},{"key":"2711_CR58","doi-asserted-by":"publisher","first-page":"H751","DOI":"10.1152\/ajpheart.01016.2006","volume":"292","author":"AM Park","year":"2007","unstructured":"Park AM, Nagase H, Vinod Kumar S, Suzuki YJ (2007) Acute intermittent hypoxia activates myocardial cell survival signaling. Am J Physiol Heart Circ Physiol 292:H751\u2013H757. https:\/\/doi.org\/10.1152\/ajpheart.01016.2006","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2711_CR59","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/cvr\/cvq361","volume":"90","author":"AM Park","year":"2011","unstructured":"Park AM, Nagase H, Liu L, Vinod Kumar S, Szwergold N, Wong CM, Suzuki YJ (2011) Mechanism of anthracycline-mediated down-regulation of GATA4 in the heart. Cardiovasc Res 90:97\u2013104. https:\/\/doi.org\/10.1093\/cvr\/cvq361","journal-title":"Cardiovasc Res"},{"key":"2711_CR60","doi-asserted-by":"publisher","first-page":"23807","DOI":"10.1074\/jbc.M302719200","volume":"278","author":"S Pikkarainen","year":"2003","unstructured":"Pikkarainen S, Tokola H, Majalahti-Palviainen T, Kerkel\u00e4 R, Hautala N, Bhalla SS, Charron F, Nemer M, Vuolteenaho O, Ruskoaho H (2003) GATA4 is a nuclear mediator of mechanical stretch-activated hypertrophic program. J Biol Chem 278:23807\u201323816. https:\/\/doi.org\/10.1074\/jbc.M302719200","journal-title":"J Biol Chem"},{"key":"2711_CR61","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.cardiores.2004.03.025","volume":"63","author":"S Pikkarainen","year":"2004","unstructured":"Pikkarainen S, Tokola H, Kerkel\u00e4 R, Ruskoaho H (2004) GATA transcription factors in the developing and adult heart. Cardiovasc Res 63:196\u2013207. https:\/\/doi.org\/10.1016\/j.cardiores.2004.03.025","journal-title":"Cardiovasc Res"},{"key":"2711_CR62","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.ejphar.2017.10.043","volume":"818","author":"K Renu","year":"2018","unstructured":"Renu K, Abilash VG, Tirupathi Pichiah PB, Arunachalam S (2018) Molecular mechanism of doxorubicin-induced cardiomyopathy\u2014an update. Eur J Pharmacol 818:241\u2013253. https:\/\/doi.org\/10.1016\/j.ejphar.2017.10.043","journal-title":"Eur J Pharmacol"},{"key":"2711_CR63","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.ejheart.2008.01.004","volume":"10","author":"A Riad","year":"2008","unstructured":"Riad A, Bien S, Gratz M, Escher F, Westermann D, Heimesaat MM, Bereswill S, Krieg T, Felix SB, Schultheiss HP, Kroemer HK, Tschope C (2008) Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice. Eur J Heart Fail 10:233\u2013243. https:\/\/doi.org\/10.1016\/j.ejheart.2008.01.004","journal-title":"Eur J Heart Fail"},{"key":"2711_CR64","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.tips.2015.03.005","volume":"36","author":"L Rochette","year":"2015","unstructured":"Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y, Vergely C (2015) Anthracyclines\/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 36:326\u2013348. https:\/\/doi.org\/10.1016\/j.tips.2015.03.005","journal-title":"Trends Pharmacol Sci"},{"key":"2711_CR65","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1210\/er.2003-0006","volume":"24","author":"H Ruskoaho","year":"2003","unstructured":"Ruskoaho H (2003) Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 24:341\u2013356. https:\/\/doi.org\/10.1210\/er.2003-0006","journal-title":"Endocr Rev"},{"key":"2711_CR66","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1161\/CIRCHEARTFAILURE.109.889642","volume":"3","author":"J Rys\u00e4","year":"2010","unstructured":"Rys\u00e4 J, Tenhunen O, Serpi R, Soini Y, Nemer M, Leskinen H, Ruskoaho H (2010) GATA4 is an angiogenic survival factor of the infarcted heart. Circ Heart Fail 3:440\u2013450. https:\/\/doi.org\/10.1161\/CIRCHEARTFAILURE.109.889642","journal-title":"Circ Heart Fail"},{"key":"2711_CR67","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.ctrv.2010.11.001","volume":"37","author":"E Senkus","year":"2011","unstructured":"Senkus E, Jassem J (2011) Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev 37:300\u2013311. https:\/\/doi.org\/10.1016\/j.ctrv.2010.11.001","journal-title":"Cancer Treat Rev"},{"key":"2711_CR68","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/bf00262581","volume":"20","author":"PA Speth","year":"1987","unstructured":"Speth PA, Linssen PC, Boezeman JB, Wessels HM, Haanen C (1987) Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients. Cancer Chemother Pharmacol 20:305\u2013310. https:\/\/doi.org\/10.1007\/bf00262581","journal-title":"Cancer Chemother Pharmacol"},{"key":"2711_CR69","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.cellsig.2011.02.007","volume":"23","author":"YJ Suzuki","year":"2011","unstructured":"Suzuki YJ (2011) Cell signaling pathways for the regulation of GATA4 transcription factor: implications for cell growth and apoptosis. Cell Signal 23:1094\u20131099. https:\/\/doi.org\/10.1016\/j.cellsig.2011.02.007","journal-title":"Cell Signal"},{"key":"2711_CR70","doi-asserted-by":"publisher","first-page":"8394","DOI":"10.1016\/j.biomaterials.2014.05.078","volume":"35","author":"MA T\u00f6lli","year":"2014","unstructured":"T\u00f6lli MA, Ferreira MP, Kinnunen SM, Rys\u00e4 J, M\u00e4kil\u00e4 EM, Szabo Z, Serpi RE, Ohukainen PJ, V\u00e4lim\u00e4ki MJ, Correia AM, Salonen JJ, Hirvonen JT, Ruskoaho HJ, Santos HA (2014) In vivo biocompatibility of porous silicon biomaterials for drug delivery to the heart. Biomaterials 35:8394\u20138405. https:\/\/doi.org\/10.1016\/j.biomaterials.2014.05.078","journal-title":"Biomaterials"},{"key":"2711_CR71","doi-asserted-by":"publisher","first-page":"H1572","DOI":"10.1152\/ajpheart.1994.266.4.H1572","volume":"266","author":"M Toth","year":"1994","unstructured":"Toth M, Vuorinen KH, Vuolteenaho O, Hassinen IE, Uusimaa PA, Lepp\u00e4luoto J, Ruskoaho H (1994) Hypoxia stimulates release of ANP and BNP from perfused rat ventricular myocardium. Am J Physiol 266:H1572\u2013H1580. https:\/\/doi.org\/10.1152\/ajpheart.1994.266.4.H1572","journal-title":"Am J Physiol"},{"key":"2711_CR72","doi-asserted-by":"publisher","DOI":"10.1242\/dev.164384","author":"M Tremblay","year":"2018","unstructured":"Tremblay M, Sanchez-Ferras O, Bouchard M (2018) GATA transcription factors in development and disease. Development. https:\/\/doi.org\/10.1242\/dev.164384","journal-title":"Development"},{"key":"2711_CR73","doi-asserted-by":"publisher","first-page":"7781","DOI":"10.1021\/acs.jmedchem.7b00816","volume":"60","author":"MJ V\u00e4lim\u00e4ki","year":"2017","unstructured":"V\u00e4lim\u00e4ki MJ, T\u00f6lli MA, Kinnunen SM, Aro J, Serpi R, Pohjolainen L, Talman V, Poso A, Ruskoaho HJ (2017) Discovery of small molecules targeting the synergy of cardiac transcription factors GATA4 and NKX2-5. J Med Chem 60:7781\u20137798. https:\/\/doi.org\/10.1021\/acs.jmedchem.7b00816","journal-title":"J Med Chem"},{"key":"2711_CR6","doi-asserted-by":"publisher","first-page":"12331","DOI":"10.1073\/pnas.1104499108","volume":"108","author":"JH van Berlo","year":"2011","unstructured":"van Berlo JH, Elrod JW, Aronow BJ, Pu WT, Molkentin JD (2011) Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 108:12331\u201312336. https:\/\/doi.org\/10.1073\/pnas.1104499108","journal-title":"Proc Natl Acad Sci USA"},{"key":"2711_CR74","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.jacc.2014.06.1167","volume":"64","author":"P Vejpongsa","year":"2014","unstructured":"Vejpongsa P, Yeh ET (2014) Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol 64:938\u2013945. https:\/\/doi.org\/10.1016\/j.jacc.2014.06.1167","journal-title":"J Am Coll Cardiol"},{"key":"2711_CR75","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.bbcan.2013.12.002","volume":"1845","author":"F Yang","year":"2014","unstructured":"Yang F, Teves SS, Kemp CJ, Henikoff S (2014) Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 1845:84\u201389. https:\/\/doi.org\/10.1016\/j.bbcan.2013.12.002","journal-title":"Biochim Biophys Acta"},{"key":"2711_CR76","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1126\/science.1151526","volume":"318","author":"J Yu","year":"2007","unstructured":"Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917\u20131920. https:\/\/doi.org\/10.1126\/science.1151526","journal-title":"Science"},{"key":"2711_CR77","doi-asserted-by":"publisher","first-page":"2768","DOI":"10.1093\/eurheartj\/ehw211","volume":"37","author":"JL Zamorano","year":"2016","unstructured":"Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM, ESC Scientific Document Group (2016) 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37:2768\u20132801. https:\/\/doi.org\/10.1093\/eurheartj\/ehw211","journal-title":"Eur Heart J"},{"key":"2711_CR78","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1038\/nm.2919","volume":"18","author":"S Zhang","year":"2012","unstructured":"Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET (2012) Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18:1639\u20131642. https:\/\/doi.org\/10.1038\/nm.2919","journal-title":"Nat Med"},{"key":"2711_CR79","doi-asserted-by":"publisher","first-page":"44735","DOI":"10.1038\/srep44735","volume":"7","author":"L Zhao","year":"2017","unstructured":"Zhao L, Zhang B (2017) Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep 7:44735. https:\/\/doi.org\/10.1038\/srep44735","journal-title":"Sci Rep"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02711-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00204-020-02711-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02711-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:14:35Z","timestamp":1615940075000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00204-020-02711-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,17]]},"references-count":80,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["2711"],"URL":"https:\/\/doi.org\/10.1007\/s00204-020-02711-8","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,17]]},"assertion":[{"value":"28 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"SMK, MJV and HR are inventors in a patent application \u201cPharmaceutical compounds\u201d (PCT\/FI2017\/050661)\u00a0concerning the compound 3i-1000 and its derivatives. No other competing interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}