Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death

Abstract

Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.

Keywords: Doxorubicin; cardiotoxicity; cell death; oxidative stress.

Figure 1

Oxidative stress-related signalling pathways involved in DOX-induced cardiomyopathy. (A-B) Roles of NOXs and NOSs in the molecular transformation of DOX. DOX is reduced to a semiquinone by NOSs and NOXs along with the generation of ROS, and RNS includes •O₂^-, H₂O₂, NO, OH^- and OH•. NO can react with •O₂^- or H₂O₂ to produce ONOO-. In addition, xanthine oxidase can also cause the generation of ONOO- via the stimulation of DOX. (C) Data show that loss of intracellular Ca²⁺ homeostasis induced by DOX contributes to the generation of free radicals. DOX phosphorylates CaMKII and prolongs the opening time of Ca²⁺ channels, leading to Ca²⁺ leakage. The increased concentration of Ca²⁺ induces the production of ROS. (D) DOX influences the integrity of mitochondrial DNA by combining with TOP2β, damaging mitochondrial function and ultimately leading to the excessive accumulation of ROS. (E) A brief overview of DOX-induced inhibition of autophagy. Abbreviations: NOXs, NADPH oxidases; NOSs, Nitric oxide synthases; ROS and RNS, Reactive oxygen and nitrogen species; •O₂^-, Superoxide; H₂O₂, Peroxide; SOD, Superoxide dismutase; NO, Nitric oxide; OH^- and OH•, Hydroxyl radical; ONOO-, Peroxynitrite anion; SR, Sarcoplasm reticulum; CaMKII, Ca/calmodulin-dependent protein kinase II; TOP2β, Topoisomerases-2β. The activation signal is indicated by the green stripe arrows, and the inhibition signal is indicated by the red stop symbols.

Figure 2

Signalling pathways involved in DOX-induced cell death. (A) The left side of the schematic diagram shows the function of PARP in cell apoptosis, which can be activated by DOX-induced DNA breaks in positive feedback and results in cell apoptosis. DOX also interacts with Top2β, forming Top2β-DOX-DNA complexes and leading to DNA apoptosis in a p53-dependent manner. (B) The picture illustrates the major steps constituting the process of pyroptosis in the caspase-3/GSDME and inflammasome/GSDMD pathways. DOX induces the activation of caspase and cleavage of PFD from the N-terminus of the GSDM family. PFD forms large pores in the membrane through oligomerization, resulting in membrane rupture and pyroptosis. (C) DOX-induced ferroptosis is dependent on lipid peroxidation and Fe²⁺ imbalance. Abbreviations: PARP, poly (ADP-ribose) polymerase; Top2β, Topoisomerases-2β; Binp-3, BH3-only protein Bcl-2/adenovirus E1B 19-kDa-interacting protein 3; TLR4, Toll like receptor 4; NLRP3, NOD-like receptor; GSDMD, Gasdermin D; GSDME, Gasdermin E; PFD, Pore-forming domain; GPX, Glutathione peroxidase; ROS, Reactive oxygen species; Acot1, Acyl-CoA thioesterase 1; Fer-1, Ferrostatin-1; GSH, Glutathione. The activation signal is indicated by the green stripe arrows, and the inhibition signal is indicated by the red stop symbols.