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To identify pharmacological features associated with TOP2-directed cardioprotection, we comparatively evaluated a chemically diverse panel of synthetic compounds, repurposed agents and natural products previously reported to modulate TOP2 activity, using dexrazoxane as the reference cardioprotectant. Recombinant human TOP2A and TOP2B inhibition was assessed by kDNA decatenation. Primary neonatal rat cardiomyocytes were pretreated with test compounds for 3\u00a0h and co-exposed to daunorubicin (DAU; 1.2 \u00b5M) for 3\u00a0h, followed by a 45-h drug-free period. TOP2 immunoreactivity was assessed after 24\u00a0h of compound exposure and DAU-induced \u03b3H2AX after 30-min pretreatment followed by 90-min DAU exposure. Effects on DAU antiproliferative activity were examined in HL-60 cells during 72-h exposure to 19 nM DAU. Dexrazoxane showed protective activity across the investigated endpoints. BNS-22 inhibited TOP2A and TOP2B with similar potency (IC\u2085\u2080 \u2248 2 \u00b5M for both isoforms) and produced the strongest protection among the experimental compounds, reducing DAU-induced LDH release by 55% at 10 \u00b5M, together with a 90% reduction in TOP2 immunoreactivity and 99.97% attenuation of DAU-induced \u03b3H2AX. BNS-22 did not attenuate DAU-induced antiproliferative activity in HL-60 cells. Resveratrol and suramin also provided significant protection at higher concentrations. Across this structurally diverse panel, biochemical TOP2 inhibition alone did not predict cardioprotection. Instead, protection was associated with a broader favourable cellular profile comprising low intrinsic toxicity, attenuation of anthracycline-induced DNA damage and, for the most effective compounds, reduced TOP2 immunoreactivity.<\/jats:p>","DOI":"10.1007\/s00204-026-04600-y","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:57:20Z","timestamp":1792792640000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological correlates of topoisomerase II-directed protection against anthracycline-induced DNA damage and cardiotoxicity: a comparative evaluation of catalytic topoisomerase II inhibitors"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-4847","authenticated-orcid":false,"given":"Jan","family":"Kube\u0161","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5377-518X","authenticated-orcid":false,"given":"Hana","family":"Jansov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0131-6010","authenticated-orcid":false,"given":"Anna","family":"Jirkovsk\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0929-7376","authenticated-orcid":false,"given":"Veronika","family":"Kereste\u0161","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9483-2925","authenticated-orcid":false,"given":"Krist\u00edna","family":"Moravov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6623-8635","authenticated-orcid":false,"given":"Daniela","family":"Hatalov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7036-5943","authenticated-orcid":false,"given":"Matthew J.","family":"Schellenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1921-5947","authenticated-orcid":false,"given":"Caroline A.","family":"Austin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4698-8379","authenticated-orcid":false,"given":"Jaroslav","family":"Roh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0145-7697","authenticated-orcid":false,"given":"Martin","family":"\u0160t\u011brba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-4176","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"\u0160im\u016fnek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"issue":"11","key":"4600_CR1","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1080\/14779072.2021.2013811","volume":"19","author":"N Bansal","year":"2021","unstructured":"Bansal N, Joshi C, Adams MJ, Hutchins K, Ray A, Lipshultz SE (2021) Cardiotoxicity in pediatric lymphoma survivors. 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