Journal
AGING-US
Volume 2, Issue 10, Pages 659-668Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100203
Keywords
Cardiac hypertrophy; doxorubicin; cardiomyocyte; cardiac differentiation; histone deacetylase inhibitor; Trichostatin A
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Funding
- Australian Institute of Nuclear Science and Engineering (AINSE)
- National Health and Medical Research Council (NHMRC)
- CRC for Biomedical Imaging Development (CRC-BID)
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Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophyassociated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by gamma H2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer.
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