Doxorubicin-Induced p53 Interferes with Mitophagy in Cardiac Fibroblasts

Abstract

Doxorubicin is a mainstay in pediatric chemotherapy treatment because of its efficacy treating leukemia and lymphoma. Unfortunately, every childhood cancer survivor will develop a chronic health problem, one of the most serious being cardiac disease. How doxorubicin damages the heart in such a way that disease progression occurs over multiple decades is still not understood.The dose of doxorubicin selected does not cause apoptosis but does arrest cell cycle. It also decreases the cells ability to migrate. Gene profiling indicated a cardiac remodeling and inflammatory profile. Mitochondria increased ROS production and underwent membrane depolarization. Secondly, the Parkin:p53 interaction mechanism was investigated. Doxorubicin was found to increase p53 expression and it was shown to sequester Parkin. As a result, mitophagy in doxorubicin-treated cells was decreased.Lastly, cardiac fibroblasts were isolated from p53 -/mice and treated with doxorubicin.The gene expression phenotype in these cells was attenuated and migration was restored. Proliferation was still decreased. Mitochondrial dysfunction was also partially attenuated. Without p53, Parkin could now localize to the mitochondria and mitophagy was restored.Doxorubicin induces a deleterious phenotype in cardiac fibroblasts that may be due to the interaction between two stress responses caused by doxorubicin's DNA and mitochondrial damage. Cardiac fibroblasts are a viable target and further research needs to be done to elucidate other harmful mechanisms at play in the fibroblast.Knowledge about the importance of cardiac fibroblasts in the development of doxorubicin-induced cardiotoxicity and a pathological mechanism broadens our

Bevacizumab-Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

“…Chemotherapy drugs also contribute to cardiomyocyte dysfunction and death by affecting mitochondrial function. For example, doxorubicin-induced upregulation of p53 inhibits protective mechanisms in cardiac fibroblast mitochondria [20], and administration of mitochondria-associated protein LRPPRC protects against doxorubicin-induced cardiac injury by inhibiting ROS production [60]. Anthracycline-mediated cardiotoxicity is also associated with dysregulation of mitochondrial metabolism, although the detailed molecular mechanisms involved are not fully understood [23].…”

“…Previous studies have reported that targeted cancer therapies, such as doxorubicin [15], anthracycline [16], and cantharidin [17], can result in cardiovascular toxicities. The adverse effects of chemotherapy drugs may result from impaired mitochondrial function, increased oxidative stress [15,18], increased mitochondria-proteasome interactions [19], impaired mitochondrial autophagy [20,21], activation of mitochondrial inflammation signaling pathways such as NF-κB [22], mitochondrial energy metabolic dysfunction [23], and mitochondrial apoptosis [24]. In addition, ER-mediated abnormalities in intracellular calcium signaling, protein misfolding as a result of ER stress, and ER-dependent cell apoptosis [25][26][27] can also contribute to cardiomyocyte damage during chemotherapy.…”