{"id":48944,"date":"2025-09-16T08:08:20","date_gmt":"2025-09-16T06:08:20","guid":{"rendered":"https:\/\/fgu.cas.cz\/udalost\/a-paradigm-shift-in-anthracycline-cardiotoxicity-topoisomerase-ii%ce%b2-mediated-dna-damage-as-a-key-target-for-cardioprotection\/"},"modified":"2025-09-16T08:09:05","modified_gmt":"2025-09-16T06:09:05","slug":"a-paradigm-shift-in-anthracycline-cardiotoxicity-topoisomerase-ii%ce%b2-mediated-dna-damage-as-a-key-target-for-cardioprotection","status":"publish","type":"udalost","link":"https:\/\/fgu.cas.cz\/en\/event\/a-paradigm-shift-in-anthracycline-cardiotoxicity-topoisomerase-ii%ce%b2-mediated-dna-damage-as-a-key-target-for-cardioprotection\/","title":{"rendered":"A Paradigm Shift in Anthracycline Cardiotoxicity: Topoisomerase II\u03b2-Mediated DNA Damage as a Key Target for Cardioprotection"},"content":{"rendered":"<p>Anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin) are potent and widely used anticancer agents belonging to topoisomerase II (Top2) poisons, but their clinical utility is limited by cardiotoxicity that can lead to heart failure. Traditionally, this adverse effect has been attributed to iron-catalyzed oxidative stress and direct myocardial injury. However, classic antioxidants and iron chelators have consistently failed to provide clinically translatable cardioprotection. Through a series of experimental studies, we have provided compelling evidence for a paradigm shift in the mechanistic understanding of anthracycline-induced cardiotoxicity. Using dexrazoxane, the only approved cardioprotectant for clinical practice and its new derivatives, we have shown that clinically translatable cardioprotection against anthracycline cardiotoxicity is based on prevention of topoisomerase II\u03b2 (<strong>Top2\u03b2)<\/strong> -dependent DNA damage in the heart instead of metal chelation and protection from direct oxidative damage. Furthermore, novel derivatives of <strong>dexrazoxane with <\/strong>enhanced potency as <strong>catalytic inhibitors of Top2\u03b2<\/strong> provided superior protection against anthracycline cardiotoxicity both <em>in vitro<\/em> and <em>in vivo<\/em>. Moreover, we have identified a novel binding site on Top2 that exhibits slight structural differences between the \u03b1 and \u03b2 isoform. This enabled the rational design of first-in-class Top2\u03b2-selective catalytic inhibitors, thereby directing the DNA damage\u2013preventing effect to postmitotic cardiomyocytes, where beta isoform of the enzyme predominates. These agents have demonstrated robust cardioprotective effects in preclinical models. In contrast, we have revealed that pharmacological inhibition of <strong>ATM-dependent DNA damage signaling <\/strong>downstream of Top2\u03b2-mediated double strand breaks significantly <strong>exacerbated anthracycline cardiotoxicity and accelerated heart failure development<\/strong>. This is particularly relevant given the ongoing clinical development of ATM inhibitors as chemosensitizers in combination with established DNA-damaging drugs. Taken together, our findings advocate a <strong>paradigm shift<\/strong> in the mechanistic understanding of anthracycline cardiotoxicity and this work paves the way for the improvement of the cardiac safety of patients undergoing anthracycline-based chemotherapy.<\/p>\n<p><strong>Biography:<\/strong> Dr. \u0160t\u011brba is Associate Professor of Pharmacology and Deputy Head of the Department of Pharmacology at the Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University. He graduated in Pharmacy (2002) and earned his PhD in Medical Pharmacology (2007), at Faculty of Pharmacy and Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, respectively. He leads the <em>CardioTox In Vivo<\/em> research laboratory, where his primary research focuses on anticancer drug-induced cardiotoxicity and heart failure, with a particular emphasis on anthracyclines. His work explores opportunities for pharmacological cardioprotection and treatment strategies. Currently, he is engaged in experimental cardio-oncology, especially investigating topoisomerase II-mediated DNA damage, DNA damage response signaling in the heart and tumors, and their pharmacological modulations. He has authored 60 publications in impact factor journals (24 as first or senior author), which have been cited over 2,500 times (excluding self-citations), and his H-index is 26 (Scopus). He serves\/served as Associate Editor of <em>ESC Heart Failure<\/em> (since 2017) and <em>Cardiovascular Toxicology<\/em> (2018\u20132023). He is also a member of the Editorial Boards of the <em>European Journal of Heart Failure<\/em> and <em>Experimental Biology and Medicine<\/em>.<\/p>\n<p><strong>Contact at IPHYS:<\/strong> Mark\u00e9ta Hlav\u00e1\u010dkov\u00e1, <a href=\"https:\/\/fgu.cas.cz\/en\/research-and-laboratories\/research-departments\/laboratory-of-developmental-cardiology\/\">Laboratory of Developmental Cardiology<\/a>, marketa.hlavackova@fgu.cas.cz<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin) are potent and widely used anticancer agents belonging to topoisomerase II (Top2) poisons, but their clinical utility is limited by cardiotoxicity that can lead to heart failure. Traditionally, this adverse effect has been attributed to iron-catalyzed oxidative stress and direct myocardial injury. However, classic antioxidants and iron chelators have consistently [&hellip;]<\/p>\n","protected":false},"author":11,"featured_media":55280,"template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"kategorie-udalosti":[84],"class_list":["post-48944","udalost","type-udalost","status-publish","has-post-thumbnail","hentry","kategorie-udalosti-lectures"],"acf":[],"_links":{"self":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/udalost\/48944","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/udalost"}],"about":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/types\/udalost"}],"author":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/users\/11"}],"version-history":[{"count":0,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/udalost\/48944\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media\/55280"}],"wp:attachment":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media?parent=48944"}],"wp:term":[{"taxonomy":"kategorie-udalosti","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/kategorie-udalosti?post=48944"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}