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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
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Pediatric doxorubicin exposure induces persistent pathological changes in mice
Jingrui Chen1, Mahder Dawit Belew1, Jing Wei1
1Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, WA 99202-2131, USA.
Toxicology and Applied Pharmacology
|October 16, 2025
Summary
Pediatric doxorubicin (DOX) chemotherapy causes long-term heart damage and mortality in mice. The inhibitor THZ1 partially protected the heart but worsened growth and survival.
Area of Science:
- Cardiovascular Research
- Pediatric Oncology
- Pharmacology
Background:
- Over 50% of pediatric cancer patients receive anthracycline chemotherapy, like doxorubicin (DOX).
- Long-term health effects of childhood DOX exposure are poorly understood, with limited protective strategies.
- Establishing a reliable preclinical model for chronic conditions in childhood cancer survivors is crucial.
Purpose of the Study:
- To develop and characterize a mouse model simulating chronic health conditions in adult survivors of childhood cancer.
- To investigate the long-term cardiac and systemic effects of pediatric doxorubicin exposure.
- To evaluate the therapeutic potential of the CDK7/12/13 inhibitor THZ1 in mitigating DOX-induced toxicity.
Main Methods:
- 14-day-old C57BL/6N mice received doxorubicin (DOX) injections twice weekly for two weeks.
- Mice were monitored for 32 weeks to assess long-term health outcomes, including cardiac function and organ weights.
- The effects of the CDK7/12/13 inhibitor THZ1 on DOX-induced toxicity were evaluated.
Main Results:
- Pediatric DOX exposure induced late-onset cardiotoxicity, characterized by systolic/diastolic dysfunction, fibrosis, and cardiomyocyte atrophy.
- DOX treatment reduced heart, liver, and spleen weights but spared lungs and kidneys, with persistent p38 activation in the heart.
- THZ1 partially alleviated cardiotoxicity but paradoxically exacerbated growth delay and accelerated mortality, also hindering weight gain and reducing organ weights.
Conclusions:
- Pediatric doxorubicin exposure leads to chronic cardiac dysfunction, underweight, and premature death in adult mice.
- Pharmacologic inhibition of CDK7/12/13 with THZ1 offers partial protection against DOX-induced cardiotoxicity.
- THZ1 treatment carries significant risks, including aggravated growth delay and increased mortality, necessitating careful consideration in therapeutic strategies.
