Shi Youyang, Li Feifei, Shen Man, Sun Chenpin, Hao Wei, Wu Chunyu, Xie Ying, Zhang Shuai, Gao Hongzhi, Yang Jianfeng, Zhou Zhongyan, Gao Dongwen, Qin Yuenong, Han Xianghui, Liu Sheng
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Cardiovasc Med. 2021 Oct 13;8:750186. doi: 10.3389/fcvm.2021.750186. eCollection 2021.
Doxorubicin (Dox) is one of the most effective chemotherapy agents used in the treatment of solid tumors and hematological malignancies. However, it causes dose-related cardiotoxicity that may lead to heart failure in patients. Luteolin (Lut) is a common flavonoid that exists in many types of plants. It has been studied for treating various diseases such as hypertension, inflammatory disorders, and cancer. In this study, we evaluated the cardioprotective and anticancer effects of Lut on Dox-induced cardiomyopathy and to explore related mechanisms in alleviating dynamin-related protein (Drp1)-mediated mitochondrial apoptosis. MTT and LDH assay were used to determine the viability and toxicity of cardiomyocytes treated with Dox and Lut. Flow cytometry was used to examine ROS levels, and electron and confocal microscopy was employed to assess the mitochondrial morphology. The level of apoptosis was examined by Hoechst 33258 staining. The protein levels of myocardial fission protein and apoptosis-related protein were examined using Western blot. Transcriptome analysis of the protective effect of Lut against Dox-induced cardiac toxicity in myocardial cells was performed using RNA sequencing technology. The protective effects of Lut against cardiotoxicity mediated by Dox in zebrafish were quantified. The effect of Lut increase the antitumor activity of Dox in breast cancer both and were further employed. Lut ameliorated Dox-induced toxicity in H9c2 and AC16 cells. The level of oxidative stress was downregulated by Lut after Dox treatment of myocardial cells. Lut effectively reduced the increased mitochondrial fission post Dox stimulation in cardiomyocytes. Apoptosis, fission protein Drp1, and Ser616 phosphorylation were also increased post Dox and reduced by Lut. In the zebrafish model, Lut significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, in the mouse model, Lut prevented Dox-induced cardiotoxicity and enhanced the cytotoxicity in triple-negative breast cancer by inhibiting proliferation and metastasis and inducing apoptosis.
阿霉素（Dox）是用于治疗实体瘤和血液系统恶性肿瘤最有效的化疗药物之一。然而，它会引起剂量相关的心脏毒性，可能导致患者心力衰竭。木犀草素（Lut）是一种存在于多种植物中的常见黄酮类化合物。它已被研究用于治疗各种疾病，如高血压、炎症性疾病和癌症。在本研究中，我们评估了Lut对阿霉素诱导的心肌病的心脏保护和抗癌作用，并探讨其减轻动力蛋白相关蛋白（Drp1）介导的线粒体凋亡的相关机制。采用MTT和LDH检测法测定经阿霉素和木犀草素处理的心肌细胞的活力和毒性。采用流式细胞术检测活性氧水平，利用电子显微镜和共聚焦显微镜评估线粒体形态。通过Hoechst 33258染色检测凋亡水平。采用蛋白质印迹法检测心肌裂变蛋白和凋亡相关蛋白的水平。利用RNA测序技术对木犀草素对阿霉素诱导的心肌细胞心脏毒性的保护作用进行转录组分析。对木犀草素减轻阿霉素介导的斑马鱼心脏毒性的保护作用进行了量化。进一步研究了木犀草素增强阿霉素对乳腺癌的抗肿瘤活性。木犀草素改善了阿霉素对H9c2和AC16细胞的毒性作用。木犀草素下调了阿霉素处理心肌细胞后的氧化应激水平。木犀草素有效减少了阿霉素刺激后心肌细胞中线粒体裂变的增加。阿霉素处理后凋亡、裂变蛋白Drp1和Ser616磷酸化也增加，而木犀草素可使其降低。在斑马鱼模型中，木犀草素显著保留了阿霉素处理后斑马鱼的心室功能。此外，在小鼠模型中，木犀草素通过抑制增殖和转移并诱导凋亡，预防了阿霉素诱导的心脏毒性，并增强了三阴性乳腺癌的细胞毒性。
