Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways
Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways
复制标题
抗贫血药物 Roxadustat (FG-4592) 通过靶向抗凋亡和抗氧化途径预防多柔比星引起的心脏毒性
DOI：
10.3389/fphar.2020.01191
复制
发表时间：
2020-08-05
影响因子：
5.6
通讯作者：
Xia, Weiwei
中科院分区：
文献类型：
--
作者：
Long, Guangfeng;Chen, Hongbing;Xia, Weiwei
多柔比星（DOX）广泛用于治疗各种恶性肿瘤。然而，其心脏毒性限制了其临床应用。Roxadustat（FG-4592）是一种新型缺氧诱导因子脯氨酰羟化酶（HIF-PHD）抑制剂，已被批准用于治疗慢性肾脏病（CKD）患者的贫血。然而，FG-4592在DOX诱导的心脏毒性中的作用仍然未知。本研究通过超声心动图、血浆LDH/CK-MB和心脏HE染色评价小鼠心脏功能。在暴露于DOX和FG-4592预处理的小鼠心脏组织和心脏细胞中评价了细胞活力、细胞凋亡、氧化应激、炎症和HIF靶基因。使用DOX敏感的HepG 2和MCF-7细胞系来评估FG-4592对DOX的抗癌活性的影响。我们发现FG-4592减轻了DOX诱导的心脏毒性，表现为对心功能障碍、心脏凋亡和氧化应激的保护，而对炎症反应没有影响。单独使用FG-4592不会改变体内心脏功能、心肌细胞形态、氧化应激和炎症。FG-4592可通过上调HIF-1α及其靶基因Bcl-2和SOD 2的表达，保护心肌细胞免受DOX诱导的凋亡和ROS的产生。重要的是，FG-4592在用或不用DOX处理的癌细胞中显示出抗癌特性。这些发现强调了FG-4592对DOX诱导的心脏毒性的保护作用，可能是通过上调HIF-1α及其靶基因拮抗凋亡和氧化应激。
Doxorubicin (DOX) is broadly used in treating various malignant tumors. However, its cardiotoxicity limits its clinical use. Roxadustat (FG-4592) is a new hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor and has been approved for treating anemia in chronic kidney diseases (CKD) patients. However, the role of FG-4592 in DOX-induced cardiotoxicity remains unknown. In this study, mouse cardiac function was evaluated by echocardiography, plasma LDH/CK-MB, and heart HE staining. Cell viability, apoptosis, oxidative stress, inflammation, and HIF-target genes were evaluated in mouse cardiac tissue and cardiac cells exposed to DOX with FG-4592 pretreatment. DOX-sensitive HepG2 and MCF-7 cell lines were used to evaluate FG-4592 effect on the anticancer activity of DOX. We found that FG-4592 alleviated DOX-induced cardiotoxicity shown by the protection against cardiac dysfunction, cardiac apoptosis, and oxidative stress without the effect on inflammatory response. FG-4592 alone did not change the cardiac function, cardiomyocyte morphology, oxidative stress, and inflammation in vivo. FG-4592 could protect cardiomyocytes against DOX-induced apoptosis and ROS production in line with the upregulation of HIF-1α and its target genes of Bcl-2 and SOD2. Importantly, FG-4592 displayed anticancer property in cancer cells treated with or without DOX. These findings highlighted the protective effect of FG-4592 on DOX-induced cardiotoxicity possibly through upregulating HIF-1α and its target genes antagonizing apoptosis and oxidative stress.