Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity

Abstract

Children surviving cancer and chemotherapy are at risk for adverse health events including heart failure that may be delayed by years. Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8–20 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced “late-onset cardiotoxicity” was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3–4 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1–45 mg/kg). Cardiovascular function was unaltered at the lower dosages (1–15 kg/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

“…In senescent cardiomyocytes, total cellular and mitochondrial ROS accumulate and induce DNA damage and repair response (17,18). Telomere shortening is the most common DNA damage feature of senescent cells (19).…”

“…The senescence of cardiomyocytes leads to cardiac hypertrophy, arrhythmia, and other types of cardiomyopathy. Importantly, the senescence of cardiomyocytes is critically involved in cardiac aging and late stage of cardiac remodeling and heart failure (18).…”

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…Its clinical use is, however, limited due to its side effects primarily the dose-dependent cardiotoxicity manifested within few days of its use. Doxorubicin also accelerates cardiomyocyte senescence leading to much delayed (by up to 20 years) heart failure and cardiotoxicity [66]. Through generation of ROS and cell cycle regulatory genes and proteins, its toxicity in cardiac and other normal cells are well-known.…”

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

“…The anthracycline doxorubicin (Dox) has been the cornerstone of anticancer therapy over the past 50 years (Andreadis et al, 2007;Tarpey et al, 2019;Shen and Cheng, 2020). However, although Dox is widely used in the treatment of various cancers with promising efficacy, it is highly toxic and can cause dosedependent irreversible serious cardiotoxicity and liver damage with long-term use (Hartmann et al, 2020;Mitry et al, 2020;Prasanna et al, 2020;Qiao et al, 2020). As a result, the clinical use of many of such chemotherapeutic agents is limited (Takagi et al, 2014;Li et al, 2015;Shi et al, 2020).…”