Affordable Access

deepdyve-link
Publisher Website

Neonatal murine engineered cardiac tissue toxicology model: Impact of dexrazoxane on doxorubicin induced injury.

Authors
  • Zhen, Juan1
  • Yu, Haitao1
  • Ji, Honglei2
  • Cai, Lu3
  • Leng, Jiyan4
  • Keller, Bradley B5
  • 1 The First Hospital of Jilin University, Changchun 130021, China; The Pediatric Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY 40292, USA. , (China)
  • 2 The First Hospital of Jilin University, Changchun 130021, China. , (China)
  • 3 The Pediatric Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY 40292, USA; Department of Radiation Oncology, the University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
  • 4 The First Hospital of Jilin University, Changchun 130021, China. Electronic address: [email protected] , (China)
  • 5 Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: [email protected]
Type
Published Article
Journal
Life sciences
Publication Date
Dec 15, 2019
Volume
239
Pages
117070–117070
Identifiers
DOI: 10.1016/j.lfs.2019.117070
PMID: 31751580
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Doxorubicin (DOX) induced cardiotoxicity is a life-threatening side effect of chemotherapy and decreased cardiac function can present years after treatment. Despite the investigation of a broad range of pharmacologic interventions, to date the only drug shown to reduce DOX-related cardiotoxicity in preclinical studies and limited clinical trials is the iron chelating agent, dexrazoxane (DRZ), although the mechanisms responsible for DRZ mediated protection from DOX related cardiotoxicity remain unclear. Engineered cardiac tissues (ECTs) can be used for tissue repair strategies and as in vitro surrogate models to test cardiac toxicities and preventative countermeasures. Neonatal murine ECTs display cardiotoxicity in response to the environmental toxin, cadmium, and reduced cadmium toxicity with Zinc co-treatment, in part via the induction of the anti-oxidant Metallothionein (MT). We adapted our in vitro ECT model to determine the feasibility of using the ECT approach to investigate DOX-related cardiac injury and DRZ prevention. We found: (1) DOX induced dose and time dependent cell death in ECTs; (2) Zinc did not show protection from DOX cardiotoxicity; (3) MT overexpression induced by Zinc, low dose Cd pretreatment, or MT-overexpression (MT-TG) did not reduce ECT DOX cardiotoxicity; (4) DRZ reduced ECT DOX induced cell death; and (5) The mechanism of DRZ ECT protection from DOX cardiotoxicity was topoisomerase 2B (TOP2B) inhibition rather than reduced reactive oxygen species. Our data support the feasibility of ECTs as an in vitro platform technology for the investigation of drug induced cardiotoxicities including the role of TOP2B in DOX toxicity and DRZ mediated DOX toxicity prevention. Copyright © 2019 Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times