Acute and Delayed Doxorubicin-Induced Myocardiotoxicity Associated with Elevation of Cardiac Biomarkers, Depletion of Cellular Antioxidant Enzymes, and Several Histopathological and Ultrastructural Changes

Abstract

Doxorubicin (DOX; Adricin) is an anthracycline antibiotic, which is an efficient anticancer chemotherapeutic agent that targets many types of adult and pediatric tumors, such as breast cancer, leukemia, and lymphomas. However, use of DOX is limited due to its cardiotoxic effects. This study sequentially investigated the mechanistic pathways of the cardiotoxic process of DOX in rats at different post-treatment periods using cumulative dose, which is used in therapeutic regimes. In this regard, 56 male albino rats were used for the experiment. The experimental animals were divided into seven groups (n = 8/group) based on dose and sacrifice schedule as follows: G1 (2 mg/kg body weight [BW] and sacrificed at day 4), G2 (4 mg/kg BW and sacrificed at day 8), G3 (6 mg/kg BW and sacrificed at day 15), G4 (8 mg/kg BW and sacrificed at day 30), G5 (10 mg/kg BW and sacrificed at day 60), G6 (10 mg/kg BW and sacrificed at day 90), and G7 (10 mg/kg BW and sacrificed at day 120). As expected, G1, G2, and G3-treated groups revealed features of acute toxic myocarditis associated with degenerative and necrotic changes in myocytes, mitochondrial damage, elevation of cardiac biomarkers, and depletion of cellular antioxidant enzymes. However, these changes increased in severity with subsequent treatment with the same dose until reaching a cumulative dose of 10 mg/kg BW for 30 d. Furthermore, after a cumulative dose of 10 mg/kg BW with a withdrawal period of 2–3 months, various predominant changes in chronicity were reported, such as disorganization and atrophy of myocytes, condensation and atrophy of mitochondria, degranulation of mast cells, and fibrosis with occasional focal necrosis, indicating incomplete elimination of DOX and/or its metabolites. Altogether, these data provide interesting observations associated with the cardiotoxic process of DOX in rats that would help understand the accompanying changes underlying the major toxic effects of the drug. Future research is suggested to explore more about the dose-dependent mechanisms of such induced toxicity of DOX that would help determine the proper doses and understand the resulting cardiomyopathy.

Glycine protects against doxorubicin-induced heart toxicity in mice

“…These marked drops might be due to increased catabolism because of declined food intake attributed to the noticed loss of appetite and fatigue. This is in agreement with Abdelatty et al ( 2021 ) and Ikewuchi et al ( 2021 ). Increases in serum urea and creatinine, as well as decreased total protein (data not shown), are supportive of the suggested increased catabolism.…”

The role of hesperidin as a cardioprotective strategy against doxorubicin-induced cardiotoxicity: The antioxidant, anti-inflammatory, antiapoptotic, and cytoprotective potentials

“…This investigation revealed a substantial elevation in all tested cardiac biomarkers; Troponin I, CK- Total, CK-MB, LDH, and AST in DOX-treated group (G2) confirming cardiotoxicity. Our findings were supported by Abdelatty et al . (2021) who reported a substantial elevation in serum cTnT, CK–MB, and AST activities in rats animal post receiving of 2, 4, or 6 mg of DOX/kg bw and increased to their highest level after being exposed to 8 mg/kg bw.…”

“…Previous investigations clarified decrease in the antioxidant enzymes level as SOD and CAT accompanied byDOX-induced cardiotoxicity ( Asensio-López et al ., 2017 ; Xiong et al ., 2018 ). And also, a substantial reduction in tissue CAT, GPX, and SOD was observed with DOX medication ( Abdelatty et al ., 2021 ). Moreover, a significant reduction in SOD levels, glutathione (GSH) activity, and increase in lipid peroxide (TBARS) levels were declared in rats treated with DOX ( Abdel-Raheem and Abdel-Ghany, 2009 ).…”

Ameliorative Effects of Bovine Lactoferrin on Benzene-Induced Hematotoxicity in Albino Rats

“…The liver is the primary organ concerned with the biotransformation of chemicals, which mostly results in markedly detrimental effects on the biochemistry of hepatocytes, such as excessive ROS generation, which causes oxidative damage not only in the liver but also in other organs, including the kidneys, spleen, and hematopoietic system (36,(43)(44)(45)(46)(47)(48)(49)(50). In this study, Bz-treated rats revealed significant increases in serum bioactivities of AST, ALT, ALP, and LDH and decreased serum total protein, albumin, and α2-and γ-globulin concentrations.…”