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Updated: Jul 24, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart
Annet N Linders1, Itamar B Dias1, Ekaterina S Ovchinnikova1
1Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Background:
Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence.
Objectives:
The aims of this study were to establish whether senescence is present in patients with doxorubicin-induced cardiotoxicity and to investigate if this could be used as a potential treatment target.
Methods:
Biopsies from the left ventricles of patients with severe doxorubicin-induced cardiotoxicity were compared with control samples. Additionally, senescence-associated mechanisms were characterized in 3-dimensional dynamic engineered heart tissues (dyn-EHTs) and human pluripotent stem cell-derived cardiomyocytes. These were exposed to multiple, clinically relevant doses of doxorubicin to recapitulate patient treatment regimens. To prevent senescence, dyn-EHTs were cotreated with the senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol.
Results:
Senescence-related markers were significantly up-regulated in the left ventricles of patients with doxorubicin-induced cardiotoxicity. Treatment of dyn-EHTs resulted in up-regulation of similar senescence markers as seen in the patients, accompanied by tissue dilatation, decreased force generation, and increased troponin release. Treatment with senomorphic drugs led to decreased expression of senescence-associated markers, but this was not accompanied by improved function.
Conclusions:
Senescence was observed in the hearts of patients with severe doxorubicin-induced cardiotoxicity, and this phenotype can be modeled in vitro by exposing dyn-EHTs to repeated clinically relevant doses of doxorubicin. The senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol prevent senescence but do not result in functional improvements. These findings suggest that preventing senescence by using a senomorphic during doxorubicin administration might not prevent cardiotoxicity.
Insights
Cellular senescence is present in doxorubicin-induced cardiotoxicity. While senomorphic drugs reduced senescence markers in heart tissue models, they did not improve cardiac function, suggesting senescence prevention may not prevent cardiotoxicity.
Area of Science:
- Cardiology
- Oncology
- Cellular Biology
Background:
- Doxorubicin is a vital chemotherapy agent, but its use is limited by cardiotoxicity.
- The precise mechanisms of doxorubicin-induced cardiotoxicity are not fully understood.
- Emerging evidence implicates cellular senescence in this process.
Purpose of the Study:
- To determine if senescence is present in patients experiencing doxorubicin-induced cardiotoxicity.
- To investigate cellular senescence as a potential therapeutic target for cardiotoxicity.
- To model doxorubicin-induced cardiotoxicity and senescence in vitro.
Main Methods:
- Compared left ventricular biopsies from patients with cardiotoxicity to controls.
- Utilized 3D dynamic engineered heart tissues (dyn-EHTs) and cardiomyocytes exposed to doxorubicin.
- Administered senomorphic drugs (5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol) to assess senescence prevention.
Main Results:
- Senescence markers were significantly elevated in patients' hearts and in vitro models.
- Doxorubicin exposure in dyn-EHTs led to senescence, tissue dilation, reduced contractility, and troponin release.
- Senomorphic drug treatment reduced senescence markers but did not improve cardiac function.
Conclusions:
- Cellular senescence is a feature of severe doxorubicin-induced cardiotoxicity.
- In vitro models successfully replicated senescence and cardiotoxicity.
- Senomorphic drugs prevented senescence but failed to restore cardiac function, indicating senescence prevention alone may not mitigate cardiotoxicity.
