Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

Abstract

Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm 2 vs. 1.36 ± 0.10 μm 2 for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine-marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was threefold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway

“…Puma contributes to p53-mediated apoptosis by indirect induction of mitochondrial outer membrane permeabilization and direct binding with Bcl-2 proteins, preventing their inhibitory effects on Bax. Moreover, DOX binds to topoisomerase IIB (TOP2B) protein and DNA, resulting in double-strand DNA breaks, as well as activating the DNA damage pathway with induction of cardiomyocyte apoptosis [ 25 ]. Normally, the cardiomyocytes attempt to repair this damage via the Neuroglin-HER2 pathway but, in the presence of Trz, an anti-HER2 binding agent, the HER2 function would be compromised, resulting in significant damage to cardiomyocytes [ 26 ].…”

Prevention of Anthracycline-Induced Cardiotoxicity: The Good and Bad of Current and Alternative Therapies

“…However, it appears that the usefulness of β-blockers against chemotherapy-related cardiotoxicity is controversial. For instance, an in vitro experimental study revealed the inability of metoprolol to prevent cardiotoxicity in C57Bl6 mice treated with Dox and trastuzumab ( 70 ). Similarly, Avila et al ( 66 ) demonstrated carvedilol's inability to mitigate ATC-induced chronic cardiotoxicity in breast cancer patients ( 67 ).…”

Mulberrin Confers Protection against Doxorubicin-Induced Cardiotoxicity via Regulating AKT Signaling Pathways in Mice

“…This drug results in cardiotoxicity, which is manifested as a progressive and irreversible cardiomyopathy [1]. The incidence of DOX-induced cardiac injury ranges from 11% to 18%, as estimated by previous studies [2,3]. The onset of DOX-induced cardiotoxicity can be acute, occurring within 2-3 days or be chronic until several months after the end of chemotherapy [3].…”