Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
Phytomedicine. 2022 Jul;101:154105. doi: 10.1016/j.phymed.2022.154105. Epub 2022 Apr 25.
Chemotherapy drugs especially anthracyclines are widely used in the treatment of hematological malignancies and solid tumors. However, their clinical application is limited by dose-dependent and irreversible heart injury, which increases the risk of congestive heart failure and heart-related mortality.
This study aims to investigate the effect and mechanism of the natural flavonoid isoorientin (ISO) combined with doxorubicin (DOX) on the proliferation of tumor cells and improve the survival rate of DOX-injured cardiomyocytes.
STUDY DESIGN/METHODS: Cardiomyocyte H9c2 and a variety of tumor cells were used to evaluate the protective effect of ISO on DOX-induced myocardial injury and enhance the anticancer effects of DOX. DOX chemotherapy-injured mice were used to evaluate the cardioprotective effect of ISO.
The antiproliferation of DOX on Hela, HepG2, HT-29, and A549 cells could be increased synergistically when cotreated with ISO in vitro. ISO could also improve the survival rate of DOX-injured cardiomyocytes by reducing reactive oxygen species, maintaining mitochondrial function, and inhibiting apoptosis. In mice receiving DOX, a protective effect on myocardial tissue, which was reflected by improved survival state of mice receiving chemotherapy, was observed. The ECG, myocardial zymogram data, HE staining, and TEM observation of myocardial tissue sections showed that ISO had a dose-dependent protective effect on the mouse hearts injured by DOX. Network pharmacology and cardiomyocyte proteomics were used to seek for related target proteins to reveal the protective mechanism of ISO on mouse models, and some potential targets (including caspase-3, EGFR, MAPK1, ESR1, CDC42, STAT1, JAK2, LCK, and CDK2) were generated. Western blotting was further used to verify that ISO upregulated Nrf2 and TGF-β3 by downregulating the phosphorylation levels of JNK and p38 proteins on the MAPK pathway and the Akt and Stat3 expression levels. The downregulation of cleaved caspase-3 and upregulation of Bcl-xl by ISO further confirmed its inhibition on caspase-dependent cardiomyocyte apoptosis.
ISO could be a potential synergistic anticancer agent with a favorable property of reducing the cardiotoxicity for DOX, and the effect mechanism could refer to the inhibition of ISO on MAPK and caspase-dependent apoptosis pathways.
化疗药物，特别是蒽环类药物，被广泛应用于血液系统恶性肿瘤和实体肿瘤的治疗。然而，由于其具有剂量依赖性和不可逆的心脏损伤，导致充血性心力衰竭和心脏相关死亡率增加，从而限制了其临床应用。
本研究旨在探讨天然类黄酮异甘草素（ISO）与阿霉素（DOX）联合应用对肿瘤细胞增殖的影响及其改善 DOX 损伤心肌细胞存活率的作用机制。
研究设计/方法：利用心肌细胞 H9c2 和多种肿瘤细胞评估 ISO 对 DOX 诱导的心肌损伤的保护作用，并增强 DOX 的抗癌作用。使用 ISO 处理 DOX 化疗损伤的小鼠，评估 ISO 的心脏保护作用。
体外实验中，ISO 与 DOX 联合处理可协同增强 DOX 对 Hela、HepG2、HT-29 和 A549 细胞的增殖抑制作用。ISO 还可以通过减少活性氧、维持线粒体功能和抑制细胞凋亡来提高 DOX 损伤心肌细胞的存活率。在接受 DOX 化疗的小鼠中，观察到 ISO 对心肌组织具有保护作用，这反映在化疗后小鼠的存活状态得到改善。心电图、心肌酶谱数据、HE 染色和心肌组织切片 TEM 观察均表明，ISO 对 DOX 损伤的小鼠心脏具有剂量依赖性的保护作用。网络药理学和心肌蛋白质组学用于寻找相关的靶蛋白，以揭示 ISO 对小鼠模型的保护机制，并产生了一些潜在的靶标（包括 caspase-3、EGFR、MAPK1、ESR1、CDC42、STAT1、JAK2、LCK 和 CDK2）。Western blot 进一步验证了 ISO 通过下调 MAPK 通路中 JNK 和 p38 蛋白的磷酸化水平以及 Akt 和 Stat3 的表达水平，上调 Nrf2 和 TGF-β3。ISO 下调 cleaved caspase-3 并上调 Bcl-xl，进一步证实其抑制 caspase 依赖性心肌细胞凋亡。
ISO 可能是一种具有降低 DOX 心脏毒性的潜在协同抗癌药物，其作用机制可能涉及 ISO 对 MAPK 和 caspase 依赖性凋亡途径的抑制作用。
