Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes

Katherine Ververis, Annabelle L. Rodd, Michelle M. Tang, Assam El-Osta, Tom C. Karagiannis

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicininduced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broadspectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential sideeffects, in relevant model systems, which may be associated with emerging combination therapies for cancer.

Original languageEnglish
Pages (from-to)4101-4114
Number of pages14
JournalCellular and Molecular Life Sciences
Volume68
Issue number24
DOIs
Publication statusPublished - Dec 2011

Keywords

  • γH2AX
  • Cardiomyocyte
  • Cardiotoxicity
  • DNA double-strand break
  • Doxorubicin
  • Histone deacetylase inhibitor
  • Sodium butyrate
  • Trichostatin A
  • Valproic acid

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