Anthracycline-induced cardiotoxicity: From pathobiology to identification of molecular targets for nuclear imaging

Abstract

Anthracyclines are a widely used class of chemotherapy in pediatric and adult cancers, however, their use is hampered by the development of cardiotoxic side-effects and ensuing complications, primarily heart failure. Clinically used imaging modalities to screen for cardiotoxicity are mostly echocardiography and occasionally cardiac magnetic resonance imaging. However, the assessment of diastolic and global or segmental systolic function may not be sensitive to detect subclinical or early stages of cardiotoxicity. Multiple studies have scrutinized molecular nuclear imaging strategies to improve the detection of anthracycline-induced cardiotoxicity. Anthracyclines can activate all forms of cell death in cardiomyocytes. Injury mechanisms associated with anthracycline usage include apoptosis, necrosis, autophagy, ferroptosis, pyroptosis, reactive oxygen species, mitochondrial dysfunction, as well as cardiac fibrosis and perturbation in sympathetic drive and myocardial blood flow; some of which have been targeted using nuclear probes. This review retraces the pathobiology of anthracycline-induced cardiac injury, details the evidence to date supporting a molecular nuclear imaging strategy, explores disease mechanisms which have not yet been targeted, and proposes a clinical strategy incorporating molecular imaging to improve patient management.

Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

“…Anthracycline compounds may induce off‐target cardiac injury. Whereas multiple pathobiological mechanisms are at play, and no single pathway can fully recapitulate all aspects of AIC, formation of a Top2β‐Dox‐DNA cleavage complex has been proposed as a key mediator of DNA DSB, transcriptional perturbation, and CM death, complicated by cardiac fibrosis and heart failure 56–58 . Biological processes and protective mechanisms operating within CM to offset anthracycline‐induced injury remain ill‐defined 59 …”

“…Whereas mechanisms are at play, and no single pathway can fully recapitulate all aspects of AIC, formation of a Top2β-Dox-DNA cleavage complex has been proposed as a key mediator of DNA DSB, transcriptional perturbation, and CM death, complicated by cardiac fibrosis and heart failure. [56][57][58] Biological processes and protective mechanisms operating within CM to offset anthracycline-induced injury remain ill-defined. 59 Whereas previously associated with an antiproliferative effect in cancer cells, [60][61][62] recent studies in triple negative breast cancer cells indicate Igfbp-3 has an obligatory role in the DNA repair response by activating EGFR and DNA-dependent protein kinase (DNA-PKcs) mediated nonhomologous end-joining (NHEJ), 63 as well as poly (ADP-ribose) polymerase-1 (PARP1) mediated DNA repair.…”

Dihydroartemisinin alleviates doxorubicin‐induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy

“…Apoptosis, necrosis, and mitochondrial dysfunction are also important in Dox-induced cardiotoxicity. 40,41 In conclusion, DHA alleviates Dox-induced cardiotoxicity and ferroptosis; furthermore, this effect is achieved by regulating autophagy to modulate the Nrf2 signal pathway.…”

In vitro evaluation of the reductive carbonyl idarubicin metabolism to evaluate inhibitors of the formation of cardiotoxic idarubicinol via carbonyl and aldo–keto reductases

“…The main dose-limiting factor in anthracycline chemotherapy is the high risk of acute and/or late-onset cardiotoxicity, which can lead to heart failure and death (Henriksen 2018 ; Jong et al 2022 ; Iarussi et al 2005 ), limiting their therapeutic use. In childhood cancer survivors, cardiovascular complications are a leading cause for morbidity and mortality (Mulrooney et al 2009 , Armenian et al 2015 ).…”