The anti-cancer drug doxorubicin induces substantial epigenetic changes in cultured cardiomyocytes

The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adver...

Full description

Saved in:
Bibliographic Details
Published in:Chemico-biological interactions 2019-11, Vol.313, p.108834-108834, Article 108834
Main Authors: Hanf, Alina, Oelze, Matthias, Manea, Adrian, Li, Huige, Münzel, Thomas, Daiber, Andreas
Format: Article
Language:English
Subjects:
Anticancer drug
Cardiomyocyte
Cardiomyopathy
Doxorubicin
Epigenetic reprogramming
Epigenetics
Oxidative stress
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts (H9c2) upon treatment with DOX (1 or 5 μM for 24 or 48 h) in adherent viable and detached apoptotic cells. The apoptosis markers cleaved caspase-3 and fractin as well as oxidative stress markers 3-nitrotyrosine and malondialdehyde were dose-dependently increased by DOX treatment. Histone deacetylases (SIRT1 and HDAC2), histone lysine demethylases (KDM3A and LSD1) and histone lysine methyltransferases (SET7 and SMYD1) were significantly regulated by DOX treatment with generation of cleaved protein fragments and posttranslational modifications. Overall, we found significant decrease in histone 3 acetylation in DOX-treated cells. DOX treatment of cultured cardiomyocyte precursor cells causes severe cell death by apoptosis associated with cellular oxidative stress. In addition, significant regulation of proteins involved in epigenetic processes and changes in global histone 3 acetylation were observed. However, the significance and clinical impact of these changes remain elusive. [Display omitted] •Doxorubicin induces oxidative stress in cultured cardiomyocytes in a dose and time-dependent manner.•Doxorubicin tends to induce apoptosis markers in cultured cardiomyocytes in a dose and time-dependent manner.•Doxorubicin induces expressional changes in epigenetic regulatory proteins.•These data may help to explain delayed cardiomyopathy observed under doxorubicin therapy.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2019.108834