Department of Cardiology, Jining Second People's Hospital, Jining 272000, China.
Department of Emergency, Liaocheng People's Hospital, Liaocheng 252000, China.
Biomed Pharmacother. 2019 Jan;109:71-83. doi: 10.1016/j.biopha.2018.07.037. Epub 2018 Nov 2.
Doxorubicin (DOX) is a wide spectrum antitumor drug. However, its clinical application is limited due to the cardiotoxicity. Carvedilol (CAR) is a β-blocker used to treat high blood pressure and heart failure. Accordingly, supplementation with natural antioxidants or plant extracts exerts protective effects against various injury in vivo. Carnosic acid (CAA), the principal constituent of rosemary, has various biological activities, including antioxidant, antitumor, and anti-inflammatory. Here, heart injury mouse model was established using DOX (20 mg/kg) in vivo. And cardiac muscle cell line of H9C2 was subjected to 0.5 μM of DOX for 24 h in vitro. Then, the protective effects of CAA and CAR alone, or the two in combination on DOX-induced cardiotoxicity in vivo and in vitro were explored. The results indicated that both CAA and CAR, when used alone, were moderately effective in attenuating DOX-induced cardiotoxicity. The combination of two drugs functioned synergistically to ameliorate cardiac injury caused by DOX, as evidenced by the significantly reduced collagen accumulation and improved dysfunction of heart. CAA and CAR exhibited stronger anti-oxidative role in DOX-treated mice partly by augmenting the expression and activities of the anti-oxidative enzymes. In addition, inflammatory response was significantly suppressed by the two in combination, proved by the decreased pro-inflammatory cytokines (COX2, TNF-α, IL-6, IL-1β and IL-18), which was associated with the inactivation of nuclear factor κB (NF-κB). Furthermore, DOX-stirred apoptosis and autophagy were dramatically attenuated by the co-treatments of CAA and CAR through down-regulating cleaved Caspase-3 and LC3B signaling pathways. The effects of CAA and CAR combination against cardiotoxicity were observed in H9C2 cells with DOX stimulation. Our findings above suggested that the use of CAR and CAA in combination could be expected to have synergistic efficacy and significant potential against cardiotoxicity induced by DOX.
多柔比星（DOX）是一种广谱抗肿瘤药物。然而，由于其心脏毒性，其临床应用受到限制。卡维地洛（CAR）是一种用于治疗高血压和心力衰竭的β受体阻滞剂。因此，补充天然抗氧化剂或植物提取物可对体内各种损伤发挥保护作用。迷迭香酸（CAA）是迷迭香的主要成分，具有多种生物学活性，包括抗氧化、抗肿瘤和抗炎作用。在这里，我们在体内使用 DOX（20mg/kg）建立了心脏损伤小鼠模型，并在体外将 DOX （0.5μM）作用于 H9C2 心肌细胞 24 小时。然后，我们探讨了 CAA 和 CAR 单独使用或两者联合使用对体内和体外 DOX 诱导的心脏毒性的保护作用。结果表明，CAA 和 CAR 单独使用时对减轻 DOX 诱导的心脏毒性均有一定效果。两种药物联合使用可协同改善 DOX 引起的心脏损伤，表现为胶原积累减少，心脏功能改善。CAA 和 CAR 在 DOX 处理的小鼠中表现出更强的抗氧化作用，部分原因是增强了抗氧化酶的表达和活性。此外，两种药物联合使用可显著抑制炎症反应，这可以通过减少促炎细胞因子（COX2、TNF-α、IL-6、IL-1β 和 IL-18）得到证明，这与核因子 κB（NF-κB）失活有关。此外，通过下调裂解 Caspase-3 和 LC3B 信号通路，CAA 和 CAR 的联合治疗可显著减轻 DOX 刺激的心肌细胞凋亡和自噬。在 DOX 刺激的 H9C2 细胞中观察到 CAA 和 CAR 联合使用对心脏毒性的作用。我们的研究结果表明，CAR 和 CAA 的联合使用可能具有协同作用，并有望对 DOX 引起的心脏毒性具有显著的治疗潜力。
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