Differential impact of doxorubicin dose on cell death and autophagy pathways during acute cardiotoxicity.

Autor: Kawalec P; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Martens MD; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Field JT; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Mughal W; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Caymo AM; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Chapman D; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Xiang B; Department of Pharmacology and Therapeutics, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Ghavami S; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Dolinsky VW; Department of Pharmacology and Therapeutics, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada., Gordon JW; Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; College Nursing, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada. Electronic address: joseph.gordon@umanitoba.ca.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2022 Oct 15; Vol. 453, pp. 116210. Date of Electronic Publication: 2022 Aug 24.
DOI: 10.1016/j.taap.2022.116210
Abstrakt: Doxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6 N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had no significant impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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