{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:14:04Z","timestamp":1791382444518,"version":"4.3.3"},"reference-count":49,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2015,2,27]],"date-time":"2015-02-27T00:00:00Z","timestamp":1424995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WO 505\/3-1"],"award-info":[{"award-number":["WO 505\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"Background and Purpose<\/jats:title>The catalytic topoisomerase II<\/jats:styled-content> inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We investigated the DNA<\/jats:styled-content> damage response and the role of the activating transcription factor 3 (ATF<\/jats:styled-content>3) accumulation in tumour cells exposed to dexrazoxane.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Dexrazoxane exposure induced topoisomerase II<\/jats:styled-content>\u03b1 (TOP2A<\/jats:styled-content>)\u2010dependent cell death, \u03b3\u2010H2AX<\/jats:styled-content> accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA<\/jats:styled-content> damage responses, shown by enhanced levels of \u03b3\u2010H2AX<\/jats:styled-content>\/53BP1<\/jats:styled-content> foci, ATM<\/jats:styled-content> (ataxia telangiectasia mutated), ATR<\/jats:styled-content> (ATM<\/jats:styled-content> and R<\/jats:styled-content>ad3\u2010related), C<\/jats:styled-content>hk1 and C<\/jats:styled-content>hk2 phosphorylation, and by p53 accumulation. Dexrazoxane\u2010induced \u03b3\u2010H2AX<\/jats:styled-content> accumulation was dependent on ATM<\/jats:styled-content>. ATF<\/jats:styled-content>3 protein was induced by dexrazoxane in a concentration\u2010 and time\u2010dependent manner, which was abolished in TOP2A<\/jats:styled-content>\u2010depleted cells and in cells pre\u2010incubated with ATM<\/jats:styled-content> inhibitor. Knockdown of ATF<\/jats:italic><\/jats:styled-content>3<\/jats:italic> gene expression by siRNA<\/jats:styled-content> triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane \u2010treated cells. This was accompanied by increased \u03b3\u2010H2AX<\/jats:styled-content> accumulation. ATF<\/jats:styled-content>3 knockdown also delayed the repair of dexrazoxane \u2010induced DNA<\/jats:styled-content> double\u2010strand breaks.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>As with other TOP2A<\/jats:styled-content> poisons, dexrazoxane induced DNA<\/jats:styled-content> double\u2010strand breaks followed by activation of the DNA<\/jats:styled-content> damage response. The DNA<\/jats:styled-content> damage\u2010triggered ATF<\/jats:styled-content>3 controlled p53 accumulation and generation of double\u2010strand breaks and is proposed to serve as a switch between DNA<\/jats:styled-content> damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13046","type":"journal-article","created":{"date-parts":[[2014,12,19]],"date-time":"2014-12-19T06:47:58Z","timestamp":1418971678000},"page":"2246-2257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["The catalytic topoisomerase II<\/scp> inhibitor dexrazoxane induces DNA<\/scp> breaks, ATF<\/scp>3 and the DNA<\/scp> damage response in cancer cells"],"prefix":"10.1111","volume":"172","author":[{"given":"Shiwei","family":"Deng","sequence":"first","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiandong","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Nikolova","sequence":"additional","affiliation":[{"name":"Institute of Toxicology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Fuhrmann","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Nemecek","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"G\u00f6dtel\u2010Armbrust","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Kaina","sequence":"additional","affiliation":[{"name":"Institute of Toxicology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Wojnowski","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Medical Center of the University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,2,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12451"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251194298"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0534"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70241-8"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803513105"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E04-08-0732"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)40754-X"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/222384a0"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003917.pub4"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70301-6"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0136"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00552-9"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0370897"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-10-668"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867305666220314194045"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.3.453"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210992200"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2727"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800050828"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/84.22.1725"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0698"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104383200"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802515200"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-2694"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.3.2137"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0080"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn550"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206611"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(03)00058-5"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.251"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-1649"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2008.10.011"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfu066"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2607"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2002.2091"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1143"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605039"},{"key":"e_1_2_10_39_1","first-page":"1460","article-title":"Chinese hamster ovary cells resistant to the topoisomerase II catalytic inhibitor ICRF\u2010159: a Tyr49Phe mutation confers high\u2010level resistance to bisdioxopiperazines","volume":"58","author":"Sehested M","year":"1998","journal-title":"Cancer Res"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1081\/DCT-120017554"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1999.17.3.880"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.4.1333"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.4.1318"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.3879"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.74"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.2"},{"key":"e_1_2_10_47_1","first-page":"3442","article-title":"Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF\u2010187 demonstrate a functional R162Q mutation in the Walker A consensus ATP binding domain of the alpha isoform","volume":"59","author":"Wessel I","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08996"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2013.02.060"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0139"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.13046","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.13046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T03:58:30Z","timestamp":1696478310000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.13046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2,27]]},"references-count":49,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,5]]}},"alternative-id":["10.1111\/bph.13046"],"URL":"https:\/\/doi.org\/10.1111\/bph.13046","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2,27]]},"assertion":[{"value":"2014-07-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-12-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-02-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}