Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation.
Cell death pathways
Doxorubicin-induced cardiotoxicity
Endogenous antioxidants
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
12
01
2022
accepted:
17
02
2022
pubmed:
26
3
2022
medline:
18
5
2022
entrez:
25
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35333943
doi: 10.1007/s00204-022-03262-w
pii: 10.1007/s00204-022-03262-w
pmc: PMC9095530
doi:
Substances chimiques
Antioxidants
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1541-1550Informations de copyright
© 2022. The Author(s).
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