Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

Abstract

Anthracyclines (ANTs) are a class of anticancer drugs widely used in oncology. However, the clinical application of ANTs is limited by their cardiotoxicity. The mechanisms underlying ANTs-induced cardiotoxicity (AIC) are complicated and involve oxidative stress, inflammation, topoisomerase 2β inhibition, pyroptosis, immunometabolism, autophagy, apoptosis, ferroptosis, etc. Ferroptosis is a new form of regulated cell death (RCD) proposed in 2012, characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. An increasing number of studies have found that ferroptosis plays a vital role in the development of AIC. Therefore, we aimed to elaborate on ferroptosis in AIC, especially by doxorubicin (DOX). We first summarize the mechanisms of ferroptosis in terms of oxidation and anti-oxidation systems. Then, we discuss the mechanisms related to ferroptosis caused by DOX, particularly from the perspective of iron metabolism of cardiomyocytes. We also present our research on the prevention and treatment of AIC based on ferroptosis. Finally, we enumerate our views on the development of drugs targeting ferroptosis in this emerging field.

Keywords: cardiotoxicity; doxorubicin; ferroptosis; iron; mechanism; treatment.

FIGURE 1

Mechanisms of ferroptosis. Ferroptosis is essentially an iron-dependent lipid peroxidation. Intracellular iron overload is a necessary condition for ferroptosis, and lipid peroxidation is the presentation form of ferroptosis. TfR1, transferrin receptor 1; FPN, ferroportin; Cys, cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; STEAP3, six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter 1; HO-1, heme oxygenase 1; NADPH, nicotinamide adenine dinucleotide phosphate; FSP1, ferroptosis suppressor protein 1; PUFA, polyunsaturated fatty acids; GCH1, GTP cyclohydrolase-1; BH4/BH2, tetrahydrobiopterin/dihydrobiopterin; LOXs, lipoxygenases; PL^•, phospholipid radical; PLOO^•, phospholipid peroxyl radical; PLOOH, phospholipid hydroperoxide; α-TOH, α-tocopherol.

FIGURE 2

The mechanisms of DIC based on ferroptosis. DOX induces ferroptosis in cardiomyocytes involves two major mechanisms: one is to disrupt iron homeostasis and the other is to promote lipid peroxidation. The targets of DOX on iron disorder are Tf, ferritin, HO-1, FXN, ABCB8, IRE, IRP, and KCNQ1OT1m6A. The targets of DOX for lipid peroxidation are ROS, SOD, GPX4, and GSH. The site of iron death in cardiomyocytes is probably the mitochondria. TfR1, transferrin receptor 1; Tf, transferrin; DOX, doxorubicin; IRP, iron regulatory protein; METTL14, methyltransferase-like 14; Nrf2, nuclear factor (erythroid-derived 2)-like 2; LIP, labile iron pool; HO-1, heme oxygenase 1; ROS, reactive oxygen species; SOD, superoxide dismutase; Cys, cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; FPN, ferroportin; FXN, frataxin; ABCB8, ABC protein-B8; O₂, oxygen; O₂^•–, active oxygen; FtMt, mitochondrial ferritin; CL, cardiolipin; OH^•, hydroxyl radical.

FIGURE 3

Prevention and SOD treatment of AIC based on ferroptosis. The mechanism of preventing ferroptosis of cardiomyocytes is mainly in two aspects. One is to inhibit iron accumulation, and the other is to inhibit lipid peroxidation. Iron chelators can play a role through the former. The effects of RTAs, anti-diabetic medications, and energy-stress inducers are mainly attributed to the latter. TfR1, transferrin receptor 1; FPN, ferroportin; DOX, doxorubicin; DNR, daunorubicin; LIP, labile iron pool; HO-1, heme oxygenase 1; ROS, reactive oxygen species; Fer-1, ferrostatin-1; DFO, deferoxamine; DXZ, dexrazoxane; PUFA, polyunsaturated fatty acids; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; EMPA, empagliflozin; Sit, sitagliptin; 2DG, 2-deoxy-d-glucose; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; HMGB1, high mobility group box 1; HO-1, heme oxygenase 1; FTH, ferritin heavy chain; NF-κB, nuclear factor-kappa B; α-TOH, α-tocopherol; CoQ10, coenzyme Q10; Lip-1, liproxstatin-1; BHT, butylated hydroxytoluene; Acot1, acyl-CoA thioesterase 1; TEMPO, 2,2,6,6-tetramethylpiperidin-N-oxyl; Met, metformin.