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Metformin-mediated protection against doxorubicin-induced cardiotoxicity

Ming-Li Sun1, Jun-Min Dong1, Chen Liu1

  • 1Phase I Clinical Trial Research Center, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|October 15, 2024
PubMed
Abstract

Insights

Metformin (MET) showed protective effects against doxorubicin (DOX)-induced cardiotoxicity in cell studies by inhibiting oxidative stress. However, this protective effect was not observed in a rat model due to adverse drug reactions.

Area of Science:

  • Cardiology
  • Pharmacology
  • Toxicology

Background:

  • A prior Phase II clinical trial investigating metformin (MET) for doxorubicin (DOX)-induced cardiotoxicity was unsuccessful.
  • Doxorubicin is a widely used chemotherapy agent known to cause significant cardiotoxicity.
  • Understanding protective mechanisms and identifying reliable indicators for MET's efficacy are crucial for future clinical applications.

Purpose of the Study:

  • To confirm MET's protective effects against DOX-induced cardiotoxicity and elucidate its mechanism in vitro using H9C2 cells.
  • To establish a Wistar rat model for DOX-induced cardiotoxicity.
  • To identify clinically relevant indicators for evaluating MET's protective potential in vivo, aiming to guide future clinical trials.

Main Methods:

  • In vitro: Assessed MET's effect on H9C2 cell viability and cytotoxicity; measured intramitochondrial reactive oxygen species (ROS) using dihydroethidium.
  • In vivo: Established a DOX-induced cardiotoxicity model in Wistar rats (n=18), divided into control, DOX, and DOX+MET groups.
  • Evaluated body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and heart tissue histopathology.

Main Results:

  • In vitro, MET demonstrated dose-dependent protection against DOX-induced cardiotoxicity in H9C2 cells, consistent with ROS inhibition.
  • The in vivo rat model of DOX-induced cardiotoxicity was successfully established.
  • MET did not show a protective effect in vivo, potentially due to adverse drug reactions like vomiting impacting energy intake.

Conclusions:

  • MET-mediated protection against DOX-induced cardiotoxicity, via inhibition of oxidative stress, was confirmed in vitro.
  • Further investigation into optimal conditions for MET's efficacy in vivo and in clinical settings is warranted.
  • Identifying and mitigating ADRs is critical for the successful clinical translation of MET for DOX-induced cardiotoxicity.
Keywords:
Cardioprotective effectDoxorubicin-induced cardiotoxicityH9C2 rat cardiomyocyte lineMetforminWistar rat

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