Molecular Mechanisms and Cardiovascular Ramifications of Doxorubicin-induced Senescence

Abstract

My dissertation delves into the emerging field of cardio-oncology, an interdisciplinary field that integrates both cardiology and oncology to mitigate chemotherapy-induced cardiovascular complications. As discussed in Chapter 1, cancer survivors confront an accelerated aging risk, making them susceptible to complications commonly seen in older populations. In the last decades, cellular senescence has been proposed as an important mechanism of premature cardiovascular complications that can be induced by cancer treatments, especially anthracyclines e.g., doxorubicin (DOX). In Chapter 2, I characterized the effects of DOX on endothelial senescence in vitro in two models of endothelial cells: primary HUVECs and immortalized EA.hy926 cells. Both exhibited similar DOX-induced senescence phenotype. Thereafter, I identified the effects of senotherapeutics, which were recently developed to mitigate the adverse effects of senescence. Both endothelial cell models responded differently to the senolytic, ABT-263, presumably due to the different expression levels of BCL-2 family proteins. In Chapter 3, metformin, an anti-diabetic drug with senomorphic properties, significantly mitigated DOX-induced endothelial senescence and the associated hyper-inflammation response to lipopolysaccharide, suggesting that metformin might serve as a protective measure against vascular aging in cancer survivors. In Chapter 4, the senescence and inflammatory responses of low DOX doses were compared between tumor-free and tumor-bearing juvenile mice. Interestingly, DOX suppressed inflammation induced by tumors, offering a unique insight into its differential impacts based on the presence or absence of a tumor. Both DOX and tumor induced organ-specific senescence. No significant changes were observed in the heart, while the liver showed the most pronounced senescence induction. An optimized tumor-bearing model using different DOX regimen was established. This model was able to capture the chemotherapeutic benefit of DOX and cardiac dysfunction. In Chapter 5, the sex-specific differences in delayed DOX-induced cardiotoxicity in mice were evaluated. Male mice were more vulnerable, exhibiting pronounced cardiac dysfunction. No sex-specific alteration in senescence markers was observed, suggesting that mechanisms other than senescence are associated with the observed sex differences. Using Cardiac proteomic analysis, several sexually dimorphic DEPs were identified, many of which are linked to acute phase proteins and are associated with the anti-inflammatory marker Il-10.