Anthracycline-induced cardiotoxicity and senescence

Abstract

Cancer continues to place a heavy burden on healthcare systems around the world. Although cancer survivorship continues to improve, cardiotoxicity leading to cardiomyopathy and heart failure as a consequence of cancer therapy is rising, and yesterday’s cancer survivors are fast becoming today’s heart failure patients. Although the mechanisms driving cardiotoxicity are complex, cellular senescence is gaining attention as a major contributor to chemotherapy-induced cardiotoxicity and, therefore, may also represent a novel therapeutic target to prevent this disease. Cellular senescence is a well-recognized response to clinical doses of chemotherapies, including anthracyclines, and is defined by cell cycle exit, phenotypic alterations which include mitochondrial dysfunction, and the expression of the pro-senescent, pro-fibrotic, and pro-inflammatory senescence-associated phenotype. Senescence has an established involvement in promoting myocardial remodeling during aging, and studies have demonstrated that the elimination of senescence can attenuate the pathophysiology of several cardiovascular diseases. Most recently, pharmacology-mediated elimination of senescence, using a class of drugs termed senolytics, has been demonstrated to prevent myocardial dysfunction in preclinical models of chemotherapy-induced cardiotoxicity. In this review, we will discuss the evidence that anthracycline-induced senescence causes the long-term cardiotoxicity of anticancer chemotherapies, consider how the senescent phenotype may promote myocardial dysfunction, and examine the exciting possibility that targeting senescence may prove a therapeutic strategy to prevent or even reverse chemotherapy-induced cardiac dysfunction.

DoxoDB: A Database for the Expression Analysis of Doxorubicin-Induced lncRNA Genes

“…Moreover, while cellular senescence is a well-recognized response to chemotherapy drugs, it has attracted attention for its connection to chemotherapy-induced cardiotoxicity. Consistently, the removal of senescent cells has been correlated with a reduction in the pathophysiology of cardiovascular disease and with the prevention of myocardial dysfunction in relation to chemotherapy-induced cardiotoxicity [ 15 , 50 , 51 , 52 , 53 , 54 ]. Furthermore, previous studies have reported DOX’s ability to induce cellular senescence in fibroblast cells, including CFs [ 55 , 56 ].…”

Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease

“…Therefore, cellular senescence can be viewed as an example of antagonistic pleiotropy, which is a cellular program which is beneficial in one setting but deleterious in another [15]. Within the cardiovascular system, models of induced and attenuated senescence have implicated senescence in the pathophysiology of myocardial remodelling (age-related, chemotherapy-induced [16], and post-injury) [3,4,[17][18][19], hypertension, atherosclerosis [20], and the development of aortic aneurysms [21], and have been extensively reviewed [22][23][24][25][26][27].…”

Anticancer drugs and cardiotoxicity: the role of cardiomyocyte and non-cardiomyocyte cells

“…Analysis of LV human heart tissue from patients with doxorubicin-induced cardiotoxicity has revealed increased expression of a range of markers of senescence in cardiomyocytes compared to LV tissue from healthy donors ( 125 ). In addition to cardiomyocytes, doxorubicin-induced senescence can potentially occur in cardiac fibroblasts and cardiac endothelial cells ( 126 ).…”