Key result
ICRF-193 inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, demonstrating superior cardioprotective efficiency against anthracycline toxicity.
Why the study?
Recent evidence suggested dexrazoxanes cardioprotective activity against anthracycline cardiotoxicity may be mediated by topoisomerase II beta inhibition or depletion rather than iron chelation.
Does ICRF-193 improve cardioprotection against anthracycline toxicity in cardiomyocytes compared to dexrazoxane?
Does ICRF-193 improve cardioprotection against anthracycline toxicity in cardiomyocytes compared to dexrazoxane?
ICRF-193 is identified as a highly potent cardioprotective agent against anthracycline toxicity due to its strong interaction with topoisomerase IIβ, outperforming the clinically approved dexrazoxane in preclinical models.
Answers are grounded in this paper and cite their sources.
ICRF-193 may offer superior TOP2B-mediated cardioprotection in preclinical models; leaves open clinical translation versus dexrazoxane.
Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure–activity relationships were demonstrated on stereoisomeric forms of 4,4′-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.
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Jirkovská et al. (2021) studied Anthracycline-induced cardiotoxicity. ICRF-193 vs. Dexrazoxane was evaluated on Cardioprotective activity and TOP2B interaction. ICRF-193 inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, demonstrating superior cardioprotective efficiency against anthracycline toxicity.
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