A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging

Abstract

The population of cancer survivors is rapidly increasing due to improving healthcare. However, cancer therapies often have long-term side effects. One example is cancer therapy-related cardiac dysfunction (CTRCD) caused by doxorubicin: up to 9% of the cancer patients treated with this drug develop heart failure at a later stage. In recent years, doxorubicin-induced cardiotoxicity has been associated with an accelerated aging phenotype and cellular senescence in the heart. In this review we explain the evidence of an accelerated aging phenotype in the doxorubicin-treated heart by comparing it to healthy aged hearts, and shed light on treatment strategies that are proposed in pre-clinical settings. We will discuss the accelerated aging phenotype and the impact it could have in the clinic and future research.

Fig. 1. Overview of mechanisms in which both doxorubicin and healthy aging can influence heart function.

Doxorubicin induces DNA damage, but also affects epigenetics and telomere length. In the cytoplasm, doxorubicin inhibits reuptake of calcium, leading to an increased calcium concentration. In the mitochondria, doxorubicin can by itself cause increased ROS production. Besides, it inhibits the electron transport chain, which leads to additional ROS production. In the nucleus chromosomes are affected by time as well. DNA damage occurs, epigenetics are altered, and telomeres become shorter. In the cytoplasm, reuptake of calcium becomes less efficient, leading to increased calcium concentrations. Age also affects the mitochondria so that the electron transport chain becomes less efficient, and more ROS is produced. All these mechanisms lead to similar outputs in the form of hypertrophy, diastolic dysfunction, increased incidence of atrial fibrillation, prolonged QT interval, and fibrosis.

Fig. 2. Pathways involved in DNA damage.

After induction of DNA damage, ATR-CHK1 and ATM-CHK2 are recruited to the damaged position. These lead to an activation and increased presence of p53, by inhibiting MDM2/4. Activated p53 in turn either binds to FOXO4, inducing increased expression of p21, or interacts with PUMA and NOXA, which activates the apoptosis cascade. Besides activation of p53, ATR-CHK1 and ATM-CHK2 are also responsible for phosphorylation of p38MAPK and transcription of p16. These two proteins activate senescence in the cell.