Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity

Philip Kawalec, View ORCID ProfileMatthew D. Martens, Jared T. Field, Wajihah Mughal, Andrei Miguel Caymo, Donald Chapman, Bo Xiang, View ORCID ProfileSaeid Ghavami, View ORCID ProfileVernon W. Dolinsky, View ORCID ProfileJoseph W. Gordon
doi: https://doi.org/10.1101/2022.01.15.476450
Philip Kawalec
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew D. Martens
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew D. Martens
Jared T. Field
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wajihah Mughal
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrei Miguel Caymo
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald Chapman
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bo Xiang
2Department of Pharmacology and Therapeutics, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saeid Ghavami
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Saeid Ghavami
Vernon W. Dolinsky
2Department of Pharmacology and Therapeutics, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Vernon W. Dolinsky
Joseph W. Gordon
1Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
3College Nursing, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
4Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Joseph W. Gordon
  • For correspondence: joseph.gordon@umanitoba.ca
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

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/6N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had little 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 Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted January 18, 2022.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity
Philip Kawalec, Matthew D. Martens, Jared T. Field, Wajihah Mughal, Andrei Miguel Caymo, Donald Chapman, Bo Xiang, Saeid Ghavami, Vernon W. Dolinsky, Joseph W. Gordon
bioRxiv 2022.01.15.476450; doi: https://doi.org/10.1101/2022.01.15.476450
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity
Philip Kawalec, Matthew D. Martens, Jared T. Field, Wajihah Mughal, Andrei Miguel Caymo, Donald Chapman, Bo Xiang, Saeid Ghavami, Vernon W. Dolinsky, Joseph W. Gordon
bioRxiv 2022.01.15.476450; doi: https://doi.org/10.1101/2022.01.15.476450

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Physiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3497)
  • Biochemistry (7341)
  • Bioengineering (5317)
  • Bioinformatics (20248)
  • Biophysics (9999)
  • Cancer Biology (7734)
  • Cell Biology (11291)
  • Clinical Trials (138)
  • Developmental Biology (6431)
  • Ecology (9943)
  • Epidemiology (2065)
  • Evolutionary Biology (13311)
  • Genetics (9358)
  • Genomics (12575)
  • Immunology (7696)
  • Microbiology (18998)
  • Molecular Biology (7432)
  • Neuroscience (40971)
  • Paleontology (300)
  • Pathology (1228)
  • Pharmacology and Toxicology (2133)
  • Physiology (3154)
  • Plant Biology (6855)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1895)
  • Systems Biology (5309)
  • Zoology (1087)