Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid

• Published in: Journal of cellular biochemistry Vol. 92; no. 2; pp. 223 - 237
• Main Authors: Marchion, Douglas C., Bicaku, Elona, Daud, Adil I., Richon, Victoria, Sullivan, Daniel M., Munster, Pamela N.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.05.2004
• Subjects: Acetylation - drug effects; breast cancer; Cell Cycle - drug effects; Cell Death - drug effects; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chromatin Assembly and Disassembly - drug effects; DNA - metabolism; DNA Damage - drug effects; DNA Topoisomerases, Type II - deficiency; DNA Topoisomerases, Type II - metabolism; Drug Synergism; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; epirubicin; Epirubicin - pharmacology; Histone Deacetylase Inhibitors; Histones - chemistry; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Microscopy, Electron; suberoylanilide hydroxamic acid; synergy; Topoisomerase II Inhibitors; topoisomerase inhibitors
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.20045

Acetylation of histones leads to conformational changes of DNA. We have previously shown that the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induced cell cycle arrest, differentiation, and apoptosis. In addition to their antitumor effects as single agents, HDAC inhibitors may cause conformational changes in the chromatin, rendering the DNA more vulnerable to DNA damaging agents. We examined the effects of SAHA on cell death induced by topo II inhibitors in breast cancer cell lines. Topo II inhibitors stabilize the topo II–DNA complex, resulting in DNA damage. Treatment of cells with SAHA promoted chromatin decondensation associated with increased nuclear concentration and DNA binding of the topo II inhibitor and subsequent potentiation of DNA damage. While SAHA‐induced histone hyperacetylation occurred as early as 4 h, chromatin decondensation was most profound at 48 h. SAHA‐induced potentiation of topo II inhibitors was sequence‐specific. Pre‐exposure of cells to SAHA for 48 h was synergistic, whereas shorter pre‐exposure periods abrogated synergy and exposure of cells to SAHA after the topo II inhibitor resulted in antagonistic effects. Synergy was not observed in cells with depleted topo II levels. These effects were not limited to specific types of topo II inhibitors. We propose that SAHA significantly potentiates the DNA damage induced by topo II inhibitors; however, synergy is dependent on the sequence of drug administration and the expression of the target. These findings may impact the clinical development of combining HDAC inhibitors with DNA damaging agents. © 2004 Wiley‐Liss, Inc.