In vitro modeling of chemotherapy-induced cardiotoxicity

This thesis discusses various aspects of cardiotoxicity induced by chemotherapy, focusing on the drugs doxorubicin and ribociclib. Cardiotoxicity is a well-known, long-term side effect of several chemotherapeutic drugs. In the first chapter, the challenges of using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) for research are discussed. These cells are often more similar to fetal cells than adult cells (immature), leading to outcomes that are divergent from adult hearts. One of the areas in which they are immature is the metabolism. In this chapter we look into the mechanisms behind this and propose ways of inducing a mature metabolism. The second and third chapter delve into the mechanisms of cardiotoxicity induced by doxorubicin and its similarities to cellular senescence. Patient-specific responses to doxorubicin were explored as well. Some patients are highly resistant to developing cardiotoxicity, while others are highly susceptible. These were compared at a molecular level. Lastly, the effect of a very new chemotherapeutic drug, ribociclib, on cardiomyocytes was investigated. It showed a similar phenotype as the doxorubicin-treated iPSC-CMs, which could be mitigated by overexpressing E2F1. The thesis finishes with a general discussion.