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Updated: Jul 29, 2025
05:14
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
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PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth
Si Chen1, Jiawei Chen1,2,3, Wenting Du1,4
1Departments of Medicine (S.C., J.C., W.D., D.M.M., C.Y.), University of Rochester School of Medicine and Dentistry, Rochester, NY.
Circulation Research
|May 26, 2023
Summary
Inhibiting PDE10A protects against doxorubicin cardiotoxicity and suppresses cancer growth. This phosphodiesterase 10A (PDE10A) inhibition offers a dual therapeutic strategy for cancer patients, reducing chemotherapy side effects and improving treatment efficacy.
Area of Science:
- Cardiovascular Biology
- Oncology
- Pharmacology
Background:
- Cyclic nucleotides (cAMP, cGMP) are crucial in cardiovascular health and disease.
- Phosphodiesterase 10A (PDE10A) hydrolyzes both cAMP and cGMP.
- PDE10A is upregulated in tumors, and its inhibition hinders cancer cell growth.
Purpose of the Study:
- To investigate the role of PDE10A in doxorubicin (DOX)-induced cardiotoxicity.
- To evaluate the impact of PDE10A inhibition on cancer progression and DOX cardiotoxicity.
Main Methods:
- Utilized PDE10A knockout mice and the inhibitor TP-10.
- Assessed DOX cardiotoxicity in mice models (C57Bl/6J and ovarian cancer xenografts).
- Conducted in vitro studies using isolated cardiomyocytes and human ovarian cancer cells.
Main Results:
- PDE10A inhibition/deficiency mitigated DOX-induced myocardial damage, apoptosis, and dysfunction.
- PDE10A inhibition reduced cancer cell viability, proliferation, and potentiated DOX effects.
- Tumor growth was attenuated, and cardiotoxicity was reduced in xenograft models with PDE10A inhibition.
- Mechanistically, PDE10A promotes DOX cardiotoxicity via Top2β, mitochondrial dysfunction, and DNA damage, while contributing to atrophy through FoxO3 signaling.
Conclusions:
- PDE10A plays a significant role in both DOX-induced cardiotoxicity and cancer growth.
- PDE10A inhibition presents a promising therapeutic strategy for cancer treatment.
- Targeting PDE10A may offer a dual benefit: preventing cardiotoxicity and inhibiting tumor progression.
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