Morphological alterations induced by doxorubicin on H9c2 myoblasts: Nuclear, mitochondrial, and cytoskeletal targets

Vilma A. Sardão, Paulo J. Oliveira, Jon Holy, Catarina R. Oliveira, Kendall B. Wallace

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Doxorubicin (Dox) is a very potent antineoplastic agent used against several types of cancer, despite a cumulative cardiomyopathy that reduces the therapeutic index for treatment. H9c2 myoblast cells have been used as an in vitro model to study biochemical alterations induced by Dox treatment on cardiomyocyte cells. Despite the extensive work already published, few data are available regarding morphological alterations of H9c2 cells during Dox treatment. The purpose of the present work was to evaluate Dox-induced morphological alterations in H9c2 myoblasts, focusing especially on the nuclei, mitochondria, and structural fibrous proteins. Treatment of H9c2 cell with low concentrations of Dox causes alterations in fibrous structural proteins including the nuclear lamina and sarcomeric cardiac myosin, as well as mitochondrial depolarization and fragmentation, membrane blebbing with cell shape changes, and phosphatidylserine externalization. For higher Dox concentrations, more profound alterations are evident, including nuclear swelling with disruption of nuclear membrane structure, mitochondrial swelling, and extensive cytoplasm vacuolization. The results obtained indicate that Dox causes morphological alterations in mitochondrial, nuclear, and fibrous protein structures in H9c2 cells, which are dependent on the drug concentration. Data obtained with the present study allow for a better characterization of the effects of Dox on H9c2 myoblasts, used as a model to study Dox-induced cardiotoxicity. The results obtained also provide new and previously unknown targets that can contribute to understand the mechanisms involved in the cardiotoxicity of Dox.

Original languageEnglish (US)
Pages (from-to)227-243
Number of pages17
JournalCell Biology and Toxicology
Volume25
Issue number3
DOIs
StatePublished - Jun 2009

Bibliographical note

Funding Information:
Acknowledgment This work was supported by NIH grant HL 58016 to K.W., by FCT grant PTDC-SAU-OSM-64084-2006 to P.J.O. and by fellowships SFRH/BD/10251/2002 and SFRH/ BPD/8359/2002 from the Portuguese Foundation for Science and Technology to V.S. and P.J.O., respectively.

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Keywords

  • Cytoskeleton
  • Doxorubicin
  • H9c2 myoblasts
  • Mitochondria
  • Nuclei

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