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Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell–derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes (EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn't. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptor protein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3. [ABSTRACT FROM AUTHOR]