title: Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes.
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 doxorubicin-induced 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 broad-spectrum 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 side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.
authors.affiliation: Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, 75 Commercial Road, Melbourne, VIC, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Ververis
authors.forename: Annabelle L
authors.initials: AL
authors.lastname: Rodd
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Tang
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Tom C
authors.initials: TC
authors.lastname: Karagiannis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D004317:Doxorubicin