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Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance


Gyöngyösi, Mariann; Lukovic, Dominika; Zlabinger, Katrin; Spannbauer, Andreas; Gugerell, Alfred; Pavo, Noemi; Traxler, Denise; Pils, Dietmar; Maurer, Gerald; Jakab, András; Riesenhuber, Martin; Pircher, Andreas; Winkler, Johannes; Bergler-Klein, Jutta (2020). Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance. Cardiovascular Research, 116(5):970-982.

Abstract

AIMS
The clinical application of doxorubicin is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of doxorubicin (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.
METHODS AND RESULTS
We treated domestic pigs with either doxorubicin, epirubicin, or liposomal doxorubicin and compared the cardiac, laboratory and hemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers NT-proBNP and Troponin I and an impact on body weight. High morbidity of epirubicin-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in doxorubicin-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes, linked to DNA damage repair and cell survival, were downregulated by doxorubicin, but upregulated by liposomal doxorubicin in both the left and right ventricle. The expression of cardioprotective translocator protein TSPO was inhibited by doxorubicin, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.
CONCLUSIONS
All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of doxorubicin induced interferon-stimulated genes in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

Abstract

AIMS
The clinical application of doxorubicin is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of doxorubicin (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.
METHODS AND RESULTS
We treated domestic pigs with either doxorubicin, epirubicin, or liposomal doxorubicin and compared the cardiac, laboratory and hemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers NT-proBNP and Troponin I and an impact on body weight. High morbidity of epirubicin-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in doxorubicin-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes, linked to DNA damage repair and cell survival, were downregulated by doxorubicin, but upregulated by liposomal doxorubicin in both the left and right ventricle. The expression of cardioprotective translocator protein TSPO was inhibited by doxorubicin, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.
CONCLUSIONS
All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of doxorubicin induced interferon-stimulated genes in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Physiology
Health Sciences > Cardiology and Cardiovascular Medicine
Health Sciences > Physiology (medical)
Language:English
Date:1 April 2020
Deposited On:16 Aug 2019 12:13
Last Modified:29 Jul 2020 11:08
Publisher:Oxford University Press
ISSN:0008-6363
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvz192
PubMed ID:31346605

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