Ming-Li Sun, Jun-Min Dong, Chen Liu, Pu Li, Chao Zhang, Jie Zhen, Wei Chen
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Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups.</p><p><strong>Results: </strong>H9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting.</p><p><strong>Conclusions: </strong>We confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117535"},"PeriodicalIF":0.0000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Metformin-mediated protection against doxorubicin-induced cardiotoxicity.\",\"authors\":\"Ming-Li Sun, Jun-Min Dong, Chen Liu, Pu Li, Chao Zhang, Jie Zhen, Wei Chen\",\"doi\":\"10.1016/j.biopha.2024.117535\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>A phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed.</p><p><strong>Objectives: </strong>The aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. 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引用次数: 0
摘要
背景：二甲双胍（MET）治疗多柔比星（DOX）所致心脏毒性的II期临床试验（NCT02472353）失败：二甲双胍（MET）治疗多柔比星（DOX）诱导的心脏毒性的II期临床试验（NCT02472353）失败：本研究的目的是利用H9C2细胞证实MET介导的对DOX诱导的心脏毒性的保护作用及其机制，并建立DOX诱导的心脏毒性Wistar大鼠模型。随后，利用Wistar大鼠确定与临床相关的指标，以评估MET介导的对DOX诱导的心脏毒性的保护作用，从而促进早日成功过渡到临床试验：方法：通过细胞活力和细胞毒性实验评估 MET 介导的保护作用。此外，还使用 ROS 荧光探针（二氢乙啶）测量了线粒体内活性氧（ROS）水平，以确认氧化应激机制。将 18 只 Wistar 大鼠随机分配到对照组、DOX 组和 DOX+MET 组，比较各组的体重、药物不良反应（ADRs）、心肌损伤、心脏功能、氧化应激和心脏组织病理学：结果：使用MET/地塞米松治疗的H9C2细胞对DOX诱导的心脏毒性具有剂量依赖性保护作用。H9C2 细胞的荧光强度表明 DOX 诱导的心肌细胞毒性和 MET 介导的对 DOX 诱导的心脏毒性的保护作用。体内实验证实，大鼠 DOX 诱导的心脏毒性模型已成功建立，但 MET 介导的对 DOX 诱导的心脏毒性的保护作用并未得到证实。这归因于呕吐等不良反应导致的能量摄入不足：我们在体外实验中证实了 MET 介导的对 DOX 诱导的心肌细胞毒性的保护作用及其抑制氧化应激的机制。当务之急是在体内或临床试验中研究MET介导的对DOX诱导的心脏毒性的保护作用的最佳条件。
Metformin-mediated protection against doxorubicin-induced cardiotoxicity.
Background: A phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed.
Objectives: The aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials.
Methods: MET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups.
Results: H9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting.
Conclusions: We confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.
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