Abstract P3118: Understanding And Overcoming Doxorubicin-Induced Cardiotoxicity Via Mitochondrial Antioxidants

• Published in: Circulation research Vol. 131; no. Suppl_1; p. AP3118
• Main Authors: Farris, Lindsey R, Yammani, Rama D, Poole, Leslie B
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 05-08-2022
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3118

Chemotherapeutic-induced cardiomyopathies have surpassed cancer as the leading cause of death in patients post-remission. The highly efficacious anti-neoplastic agent, Doxorubicin (DOX), is a major culprit of dose-limiting cardiotoxicity, though the method of insult is not completely understood. While cardiotoxicity is likely multifaceted, a route of interest is the upregulation of reactive oxygen species (ROS) that leads to mitochondrial damage and other cellular complications within cardiomyocytes. Cardiomyocytes are heavily reliant on their mitochondria as the source of cellular energy, as 30% of cell volume is taken up by the organelle. To understand and counter ROS accumulation in the mitochondria with DOX administration, we are investigating the role of mitochondrially targeted antioxidants. We have found that DOX increases cytotoxicity and caspase-3 cleavage in cardiomyoblasts in vitro while inhibiting activation of nuclear factor erythroid 2-related factor 2 (Nrf2) which plays an important role in cellular antioxidant response. We have also found MitoQ, an analog of coenzyme Q, to be protective against DOX cytotoxicity in cell culture. To further evaluate MitoQ ability to mitigate DOX cardiotoxicity, we are investigating the mechanism of action via the Keap1/Nrf2 pathway, interplay with DOX anti-cancer efficacy, and in vivo therapeutic potential. The endogenous mitochondrial peroxiredoxin, Prx3, has been implicated as an important player in both tumor growth and ROS management in disease models, and it has been shown to be upregulated in the hearts of mice as well as in H9C2 cardiomyoblasts after DOX exposure. We aim to understand how the high ROS environment created by DOX-administration leads to potential post-translational modification of Prx3, thus affecting its role as a possible signaling protein. The interactions between MitoQ and Prx3 will also be elucidated. These in vitro studies will guide future in vivo experimentation to further understand DOX cardiotoxicity and evaluate a potential adjuvant therapeutic.