Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Can J Cardiol. 2016 Dec;32(12):1513-1519. doi: 10.1016/j.cjca.2016.06.002. Epub 2016 Jun 20.
In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity. Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology, we still do not have an optimal antioxidant for the prevention of DOX + TRZ-mediated cardiac dysfunction. The objective of this study was to investigate whether the novel antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ-induced heart failure in a murine model.
A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1) saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX + TRZ, (6) NACA + DOX, (7) NACA + TRZ, and (8) NACA + DOX + TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were killed for histologic and biochemical analyses.
In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from 73% ± 4% to 43% ± 2% on day 10. In mice receiving DOX + TRZ, the LVEF decreased from 72% ± 3% to 32% ± 2% on day 10. Prophylactic administration of NACA to mice receiving DOX or DOX + TRZ was cardioprotective, with an LVEF of 62% ± 3% and 55% ± 3% on day 10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX + TRZ, which was attenuated by the prophylactic administration of NACA.
NACA attenuated the cardiotoxic side effects of DOX + TRZ in a murine model of chemotherapy-induced cardiac dysfunction by decreasing OS and apoptosis.
在乳腺癌治疗中，包括多柔比星（DOX）和曲妥珠单抗（TRZ）在内的抗癌疗法会显著增加心脏毒性的风险。尽管越来越多的证据表明氧化应激（OS）在其病理生理学中起作用，但我们仍然没有一种最佳的抗氧化剂来预防 DOX+TRZ 介导的心脏功能障碍。本研究的目的是研究新型抗氧化剂 N-乙酰半胱氨酸酰胺（NACA）是否可以减轻 DOX+TRZ 诱导的小鼠模型心力衰竭。
共 100 只 C57Bl/6 雌性小鼠接受以下 1 种药物治疗方案之一：（1）生理盐水，（2）NACA，（3）DOX，（4）TRZ，（5）DOX+TRZ，（6）NACA+DOX，（7）NACA+TRZ 和（8）NACA+DOX+TRZ。在 10 天的研究期间进行了连续的超声心动图检查，之后处死小鼠进行组织学和生化分析。
接受 DOX 治疗的小鼠左心室射血分数（LVEF）从第 10 天的 73%±4%降至 43%±2%。接受 DOX+TRZ 治疗的小鼠 LVEF 从第 10 天的 72%±3%降至 32%±2%。预防性给予 NACA 可保护接受 DOX 或 DOX+TRZ 治疗的小鼠，第 10 天的 LVEF 分别为 62%±3%和 55%±3%。组织学和生化分析表明，在接受 DOX+TRZ 治疗的小鼠中，细胞完整性丧失、OS 增加和心脏细胞凋亡增加，而预防性给予 NACA 可减轻这些变化。
NACA 通过减少 OS 和细胞凋亡，减轻了 DOX+TRZ 在化疗诱导的心脏功能障碍小鼠模型中的心脏毒性副作用。
