ORCID

0009-0005-5596-0601

Keywords

Apoptosis, Cisplatin, Cardiac Dysfunction, Cisplatin-induced Cardiotoxicity, Necroptosis, Reactive Oxygen Species

Abstract

Cisplatin is an alkylating agent which is used extensively to treat numerous types of cancers, with an estimated 500,000 cancer patients eligible for treatment with Cisplatin in the US. Cisplatin has proven itself as an extremely effective anticancer agent, for example, Cisplatin increased the survival rate of testicular cancer from 10% to 90%. However, the prevalence of Cisplatin-induced cardiotoxicity (CIC), an adverse effect of Cisplatin treatment, is of major concern. The mechanisms involved in Cisplatin-induced cardiotoxicity are unknown. Therefore, in this study we investigated upregulation of reactive oxygen species (ROS) activating downstream cell death pathways apoptosis and necroptosis, as a mechanism of CIC. Using C57/BL6 mice were divided into 2 groups: Control (Saline), and Cisplatin. On D29, echocardiography was performed and mice sacrificed. Heart tissue samples were analyzed for ROS, apoptosis, necroptosis and necroinflammation markers with dihydroethidium (DHE) staining, immunohistochemistry, and western blotting. Histological staining was performed to determine cardiac hypertrophy and cardiac fibrosis. We observed a substantial (p< 0.05) increase in ROS in Cisplatin mice. Further, we found a significant (p< 0.05) increased expression of pro-apoptotic markers BAX, caspase-3, p53, and a considerable decrease (p< 0.05) in anti-apoptotic marker BCL-2 in Cisplatin-treated mice. A significant (p< 0.05) increase in necroptotic markers RIPK1, RIPK3, MLKL and a significant increase in necroinflammation markers IL-1α, and IL-33 were observed in Cisplatin-treated mice. Furthermore, we observed a significant increase (p< 0.05) in damage-associated molecular patterns (DAMPs), HMGB1, and TNF-α in Cisplatin-treated mice. In addition, we found a sizeable (p< 0.05) increase in cardiomyocyte hypertrophy and fibrosis in Cisplatin-treated mice. Finally, we found that in Cisplatin-treated mice there was a significant increase (p< 0.05) in cardiac dysfunction compared to control mice. In conclusion, we report that Cisplatin generates ROS, triggering both apoptosis and necroptosis, causing adverse cardiac remodeling, culminating in overall cardiac dysfunction.

Completion Date

2025

Semester

Summer

Committee Chair

Singla, Dinender

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Release Date

8-15-2027

Document Type

Thesis

Campus Location

Orlando (Main) Campus

Subjects

Cisplatin--Toxicology; Cardiovascular toxicology; Heart--Diseases--Chemotherapy; Antineoplastic agents--Toxicology; Active oxygen--Toxicology

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Available for download on Sunday, August 15, 2027

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