Abstract
Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.
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The data that has been used is confidential. The data referred to in this study were obtained from the corresponding authors.
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Acknowledgements
We are grateful to Dr. Yangqiu Li, Dr. Aibin He, and Dr. Xufeng Qi for critically reading the manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81970143 and No. 82270167), the Talent Young Program of Guangdong Province (2021B1515020017), the Municipal School Joint Programme from Guangzhou Science and Technological Project (202201020012), and the Leading Talents Program from The First Affiliated Hospital of Jinan University to HZ.
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Conceptualization: HZ; methodology: XFS, FSL, NHY, SQD, DWY; investigation: HZ, JD, HM, HW; visualization: XFS, NHY, JD; funding acquisition: HZ; project administration: HZ; supervision: HZ, JD, EFS; resources: DWY, EFS; writing original draft: XFS, JD; writing review & editing: HZ, JD, EFS.
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All animal experiments were performed in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals, the National Institute of Health guidelines, and the ARRIVE guidelines on ethics. The study was authorized by the Animal Studies Committee of Jinan University (Guangzhou, China) and performed in accordance with the guidelines issued by the committee.
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Highlights
• Autophagy is triggered during DOX-induced cardiotoxicity.
• Atg7 deficiency attenuates DOX-induced cardiac dysfunction in vivo.
• VPS34 inhibitor SAR405 provided protection against DOX-induced cardiotoxicity by inhibiting autophagy in vitro and in vivo.
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Sun, X., Du, J., Meng, H. et al. Targeting autophagy with SAR405 alleviates doxorubicin-induced cardiotoxicity. Cell Biol Toxicol 39, 3255–3267 (2023). https://doi.org/10.1007/s10565-023-09831-8
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DOI: https://doi.org/10.1007/s10565-023-09831-8