2. Academic Validation
  3. Metformin-mediated protection against doxorubicin-induced cardiotoxicity

Metformin-mediated protection against doxorubicin-induced cardiotoxicity

  • Biomed Pharmacother. 2024 Nov:180:117535. doi: 10.1016/j.biopha.2024.117535.
Ming-Li Sun 1,  Jun-Min Dong 2,  Chen Liu 2,  Pu Li 2,  Chao Zhang 3,  Jie Zhen 4,  Wei Chen 5
Affiliations

Affiliations

  • 1 Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China. Electronic address: sunmingli@bjsjth.cn.
  • 2 Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
  • 3 Department of Ultrasonography, Beijing Chaoyang Hospital affiliated to Capital Medical University, Beijing 100020, China.
  • 4 Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
  • 5 Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China. Electronic address: hanwa63@126.com.
PMID: 39405911 DOI: 10.1016/j.biopha.2024.117535
Abstract

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.

Keywords

Cardioprotective effect; Doxorubicin-induced cardiotoxicity; H9C2 rat cardiomyocyte line; Metformin; Wistar rat.

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