Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Peng, Tianqing

Abstract

Drug-induced cardiotoxicity is a life-threatening side effect of anti-cancer treatment. Doxorubicin (DOX) is a widely used chemotherapeutic that induces cancer cell death through reactive oxygen species (ROS) production and topoisomerase IIα inhibition. Unfortunately, its usage has been demonstrated to worsen cardiac outcomes in cancer patients. Thus, there is a need for biomarkers to predict cardiotoxicity and create preventative interventions for DOX-induced cardiac injury. SerpinA3 is a target of clinical interest due to its overexpression in various cancers. However, it remains unknown if serpinA3 plays a role in cardiotoxicity. Here, we elucidated the role of serpinA3 in DOX-induced cardiotoxicity in both a human ventricular cardiomyocyte model and a murine primary cardiomyocytes model. DOX incubation resulted in an increase in serpinA3 expression in cardiomyocytes. It was linked to the excess production of mitochondrial ROS due to DOX treatment. Importantly, the increase in serpinA3 expression was correlated with a decrease in cardiotoxicity of cardiomyocytes. These findings highlight the critical role of serpinA3 in cardiomyocytes undergoing DOX-induced injury, and the potential of serpinA3 as a biomarker to predict cardiac injury development in patients receiving chemotherapy.

Summary for Lay Audience

Doxorubicin is an effective and widely used chemotherapy drug to treat various cancers. The drug effectively kills cancer cells through oxidative stress, a process in which harmful molecules known as reactive oxygen species are produced to damage the cells. Unfortunately, a significant downside to doxorubicin is its potential to cause life-threatening heart damage to cancer patients if they receive high doses of the drug. These adverse effects limit the drug’s usage and urge the current need for biomarkers to predict this outcome in the body. Recent research has focused on serpinA3, a protein highly expressed in various cancers, to study chemotherapy-induced heart damage. In this thesis, we studied the effects of serpinA3 levels following doxorubicin treatment. We found that doxorubicin treatment increased the levels of serpinA3 in heart cells. The increase in serpinA3 levels was correlated with the production of reactive oxygen species, a process that occurs when there is damage to the cells. Interestingly, higher serpinA3 expression in the heart cells appeared to reduce the damage caused by doxorubicin, suggesting that serpinA3 could serve as a protective factor. Our findings propose that serpinA3 may be a valuable marker for predicting and potentially mitigating doxorubicin-induced heart injury in cancer patients receiving chemotherapy.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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Available for download on Friday, August 29, 2025

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