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The cytotoxic inhibitory concentration 50 (IC<jats:sub>50<\/jats:sub>) of the investigated steroids was determined against H1299, CaCo2, MDA\u2010MB\u2010468, and FaDu cancer cell lines and compared to Dox. Fluticasone propionate and fusidic acid exhibited the most potent antiproliferative effect against the MDA\u2010MB\u2010468 with IC<jats:sub>50<\/jats:sub> values of 10.4\u2009\u00b1\u20090.7 and 10.6\u2009\u00b1\u20091.7\u2009\u03bcM, respectively. On the other hand, the outstanding antitumor members (beclomethasone dipropionate, fluticasone propionate, prednisolone, dexamethasone, and fusidic acid) were further investigated for their TOP II inhibitory potentials. Where the protein expression of TOP II was downregulated by 0.79, 0.76, and 0.67\u2010fold change for fusidic acid, fluticasone propionate, and dexamethasone, respectively, compared to the control. Besides, the examined steroidal candidates were subjected to a molecular docking study towards the TOP II receptor in comparison to Dox and the co\u2010crystallized ligand (EVP) as references. Moreover, molecular dynamics (MD) simulations were conducted on the aforementioned steroids along with Dox and EVP for 200\u2009ns to validate the docking results. Consequently, steroids, in particular fusidic acid, fluticasone propionate, and dexamethasone, can be regarded as promising lead compounds targeting TOP II for cancer treatment along with their typical anti\u2010inflammatory effects.<\/jats:p>","DOI":"10.1002\/ddr.70152","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T13:10:53Z","timestamp":1757077853000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Topoisomerase II Inhibitory Potential of Steroidal Drugs as a Recommended Mechanism of Action for Their Anticancer Activity: <i>In Silico<\/i> and <i>In Vitro<\/i> Assessments"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-6073","authenticated-orcid":false,"given":"Ahmed A.","family":"Al\u2010Karmalawy","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy The University of 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