Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation

Abstract

A breakthrough in oncology research was the discovery of doxorubicin (Dox) in the 1960’s. Unlike other chemotherapy drugs, Dox was determined to have a greater therapeutic index. Since its discovery, Dox has, in part, contributed to the 5–10-year survival increase in cancer patient outcomes. Unfortunately, despite its efficacy, both in adult and pediatric cancers, the clinical significance of Dox is tainted by its adverse side effects, which usually manifest as cardiotoxicity. The issue stems from Dox’s lack of specificity which prevents it from accurately distinguishing between cancer cells and healthy cell lines, like cardiomyocytes. In addition, the high binding affinity of Dox to topoisomerases, which are abundantly found in cancer and cardiac cells in different isoforms, potentiates DNA damage. In both cell lines, Dox induces cytotoxicity by stimulating the production of pro-oxidants whilst inhibiting antioxidant enzymatic activity. Given that the cardiac muscle has an inherently low antioxidant capacity makes it susceptible to oxidative damage thereby, allowing the accumulation of Dox within the myocardium. Subsequently, Dox drives the activation of cell death pathways, such as ferroptosis, necroptosis and apoptosis by triggering numerous cellular responses that have been implicated in diseases. To date, the exact mechanism by which Dox induces the cardiotoxicity remains an aspect of much interest in cardio-oncology research. Hence, the current review summarizes the proposed mechanisms that are associated with the onset and progression of DIC.

Protective Effects of Amauroderma rugosum on Doxorubicin-Induced Cardiotoxicity through Suppressing Oxidative Stress, Mitochondrial Dysfunction, Apoptosis, and Activating Akt/mTOR and Nrf2/HO-1 Signaling Pathways

“…Oxidative stress is considered to be one of the main causes of Dox-induced cardiac injury [ 23 ] as an imbalance between ROS and antioxidants can lead to oxidative stress [ 24 , 25 ]. Sustained oxidative stress caused by Dox can reduce the mitochondrial membrane potential, which induces mitochondrial dysfunction and cell apoptosis and ultimately leads to cardiomyocyte damage [ 26 ].…”

Molecular mechanisms associated with the chemoprotective role of protocatechuic acid and its potential benefits in the amelioration of doxorubicin-induced cardiotoxicity: A review

“…Other common forms of DOX-induced death of cardiomyocytes include necroptosis, pyroptosis, and ferroptosis [11] . Although beneficial to the cell under physiological conditions due to its role in the normal development of cardiomyocytes and the establishment of cardiac homeostasis, apoptosis becomes dysregulated and cardiotoxic following DOX-treatment, ultimately inducing cell death, genome instability, and clinically detectable DIC [8] . Notably, DOX-induced apoptosis could be via any of the two canonical pathways—intrinsic and extrinsic pathways.…”

“…The induction of the intrinsic pathway following DOX treatment is crucially accompanied by mitochondrial outer membrane permeabilization (MOMP). This represents a loss in the mitochondrial membrane potential and is commonly referred to as the ‘point-of-no return’ along the intrinsic pathway of the apoptosis [8] , [94] . Once established, the MOMP, triggers the release of cytochrome c (Cyt c), an intracellular mitochondrial protein that mediates the trafficking of electrons between complex III and complex IV into the cytosol.…”

“…Stimulation of pro-oxidant mechanisms and inhibition of antioxidant enzyme activity have been recently identified as the fundamental molecular mechanisms underlying DIC [6] , [8] , [9] , [12] . Moreover, once accumulated in the myocardium, DOX begins to activate cell-death pathways such as ferroptosis, necroptosis, and apoptosis which manifest in the clinical cardiotoxicity [8] , [11] .…”

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

“…This is because Dox either suppresses autophagy, resulting in the accumulation of damaged organelles which trigger oxidative stress and inflammation, or increases autophagic response to accelerate the removal of useful cellular components via apoptosis ( 13 , 32 , 40 ). Similarly, the upregulation of autophagy markers like light chain 3B (LC3B) has been previously shown to directly interact with receptor-interacting protein-1 (RIPK1) and RIPK3, which promote the formation of necrosomes in the presence of death receptors, such as Fas and tumor necrosis factor receptor 1 (TNFR1), thereby inducing necroptosis ( 28 , 41 , 42 ).…”