Abstract
Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.
Highlights
Due to improved treatment regimens, by 2020 there will be over 500,000 childhood cancer survivors in the U.S [1] by age 50 over half of these long-term survivors will suffer from at least one debilitating or even fatal chronic health condition [2]
While childhood cancer survivors suffer from chronic cardiotoxicity, acute toxicity has essentially been eliminated in this population due a strict adherence to lifetime cumulative dose limits [10, 11]
Dysfunction of the various cells of the heart due to DOX exposure could lead to aberrant growth and maturation
Summary
Due to improved treatment regimens, by 2020 there will be over 500,000 childhood cancer survivors in the U.S [1] by age 50 over half of these long-term survivors will suffer from at least one debilitating or even fatal chronic health condition [2]. DOX toxicity manifests differently in cancer survivors treated as adults versus those treated in childhood [8, 9]. A barrier to understanding the pathologic mechanisms of chronic DOX cardiotoxicity in survivors of pediatric cancer is the long latent period between exposure and development of cardiac disease. While childhood cancer survivors suffer from chronic cardiotoxicity, acute toxicity has essentially been eliminated in this population due a strict adherence to lifetime cumulative dose limits [10, 11]. At the time of DOX exposure, children are undergoing cardiac growth and maturation [12]. Dysfunction of the various cells of the heart due to DOX exposure could lead to aberrant growth and maturation.
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