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Review
. 2024 Oct;29(5):666-680.
doi: 10.1016/j.cstres.2024.09.001. Epub 2024 Sep 27.

The mechanism and therapeutic strategies in doxorubicin-induced cardiotoxicity: Role of programmed cell death

Yanzhao Li  1 , Jing Yan  2 , Pingzhen Yang  2
Affiliations
Review

The mechanism and therapeutic strategies in doxorubicin-induced cardiotoxicity: Role of programmed cell death

Yanzhao Li et al. Cell Stress Chaperones. 2024 Oct.

Erratum in

Abstract

Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that programmed cell death plays a significant role in DOX-induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, oxidative stress, inflammation, and mitochondrial dysfunction are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathways of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including sirtuin deacetylase (silent information regulator 2 [Sir2]) 1 (SIRT1)/nuclear factor erythroid 2-related factor 2, SIRT1/Klotho, SIRT1/Recombinant Sestrin 2, adenosine monophosphate-activated protein kinase, AKT, and peroxisome proliferator-activated receptor. Heat shock proteins function as chaperones, which play an important role in various stressful situations, especially in the heart. Thus, some of heat shock proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above.

Keywords: Cardiotoxicity; Doxorubicin; Heat shock protein; Programmed cell death; Therapeutic strategies.

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Figures

Fig. 1
Fig. 1
Schematic diagram of the mechanism of apoptosis, pyroptosis, and necroptosis. Abbreviations used: DOX, doxorubicin; METRNL, Meteorin-like; SIRT1, sirtuin deacetylase (silent information regulator 2 [Sir2]) 1; DAXX, death domain-associated protein; IL, interleukin; TOP-2β, topoisomerase 2β; PDE10A, phosphodiesterase 10A; PARP, nuclear enzyme poly (ADP-ribose) polymerase; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; TLR4, toll-like receptor 4; GSDMD, gasdermin D; Bnip3, BH3-only protein Bcl-2/adenovirus E1B 19-kDa-interacting protein 3; NLRP3, nucleotide-binding domain-like receptor protein 3; GSK-3β, glycogen synthase kinase 3β; TNF-α, tumor necrosis factor-alpha; CAMKII, calcium/calmodulin-dependent protein kinase II association domain; RIPK, receptor-interacting serine/threonine-protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1-alpha; MLKL, mixed lineage kinase domain-like protein; TRADD, tumor necrosis factor receptor type 1 associated death domain protein; FADD, Fas-associated protein with death domain; Bcl-2, B-cell lymphoma 2.
Fig. 2
Fig. 2
Schematic diagram of the mechanism of autophagy and ferroptosis. Abbreviations used: DOX, doxorubicin; Bnip3, BH3-only protein Bcl-2/adenovirus E1B 19-kDa-interacting protein 3; ROS, reactive oxygen species; TFEB, transcription factor EB; LCN2, lipocalin-2; GSDMD, gasdermin D; FAM134B, an endoplasmic reticulum autophagy receptor; LC3, autophagic protein; SIRT, sirtuin deacetylase (silent information regulator 2 [Sir2]); RRM2, ribonucleotide reductase M2 subunit; Lamp2A, lysosomal-associated protein 2a; Alas1, aminolevulinate synthase 1; 5-ALA, 5-aminolevulinic acid; GPX4, glutathione peroxidase 4; SLC7A11, solute carrier family 7 member 11; EP1, E-prostanoid 1 receptor; PRMT4, protein arginine methyltransferase 4; Nrf2, nuclear factor erythroid 2-related factor 2; CYLD, cylindromatosis; SPATA2, spermatogenesis-associated protein 2; Bcl-2, B-cell lymphoma 2.
Fig. 3
Fig. 3
Schematic representation of the role of oxidative stress, inflammation, and mitochondrial dysfunction in DOX-induced cardiotoxicity. Abbreviations used: DOX, doxorubicin; Nrf2, nuclear factor erythroid 2-related factor 2; RIPK1, receptor-interacting serine/threonine-protein kinase 1; KNG1, kininogen-1; FNDC5, fibronectin type III domain-containing 5; MON, monotropein; ROS, reactive oxygen species; NLRP3, nucleotide-binding domain-like receptor protein 3; ASC, apoptosis-associated speck-like protein containing a CARD; NF-κB, nuclear factor-κB; GSDMD, gasdermin D; AMPK, adenosine monophosphate-activated protein kinase; NOX, nicotinamide adenine dinucleotide phosphate oxidase; DRP1, dynamin-related protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1-alpha; Bnip3, Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3; mPTP, mitochondrial permeability transition pore; cypD, cyclophilin D; FIS1, mitochondrial fission 1 protein.
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