Department of Cardiology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang, China; The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
Biomed Pharmacother. 2020 Oct;130:110534. doi: 10.1016/j.biopha.2020.110534. Epub 2020 Jul 22.
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.
多柔比星（DOX）以其强大的抗肿瘤活性而闻名，但由于其多种严重的不良反应而受到限制。一个主要的不良反应是急性心脏毒性；然而，其机制尚未阐明。褐藻糖胶是一种多功能且无毒的多糖，由于其良好的生物活性和安全性而被广泛研究。因此，我们提出褐藻糖胶可能在不引起额外副作用的情况下对 DOX 诱导的急性心脏毒性发挥保护作用。通过腹腔注射单次高剂量 DOX 诱导大鼠急性心脏损伤。在 DOX 注射前给予褐藻糖胶口服，并应用 JAK2 抑制剂 AG490 来验证 JAK2/STAT3 途径的参与。在体外，用相同的药物在不同的浓度和干预时间处理 H9C2 细胞。体内和体外结果表明，DOX 给药诱导心肌损伤，伴有心脏组织或细胞中加速凋亡和自噬不足，褐藻糖胶补充可显著改善这种情况。AG490 部分消除了褐藻糖胶的心脏保护作用，表明 JAK2 信号的参与。此外，Western blot 显示 DOX 诱导 JAK2/STAT3 通路激活，褐藻糖胶增强，AG490 减弱。因此，褐藻糖胶通过增强自噬和抑制凋亡，以 JAK2/STAT3 依赖的方式对 DOX 诱导的心脏毒性产生有利影响，这可能为对抗负面化疗诱导的影响提供一种有前途的新治疗策略。
