The effects of the histone deacetylase inhibitor romidepsin (FK228) are enhanced by aspirin (ASA) in COX-1 positive ovarian cancer cells through augmentation of p21.

Son DS, Wilson AJ, Parl AK, Khabele D
Cancer Biol Ther. 2010 9 (11): 928-35

PMID: 20404564 · PMCID: PMC4047717 · DOI:10.4161/cbt.9.11.11873

Histone deacetylase (HDAC) inhibitors have shown preclinical efficacy in solid tumors, including ovarian cancers. Our group has published that the HDAC inhibitor, romidepsin (FK228) suppresses ovarian cancer cell growth at nanomolar concentrations in vitro. HDAC inhibitors appear to be even more effective when used in combination with other antitumor agents. However, it remains unclear which antitumor agents are best suited for combination therapy. A recent report suggested that aspirin (acetylsalicylic acid, ASA ) is synergistic with HDAC inhibitors in ovarian cancer cells. ASA is a relatively selective inhibitor of cyclooxygenase-1 (COX-1) and has anti-proliferative effects in ovarian cancer cells. The goal of this study was to investigate the impact of ASA on the activity of the HDAC inhibitor, FK228 in COX-1 positive (OVCAR-3) and COX-1 negative (SKOV-3) human ovarian cancer cell lines. The growth inhibitory effects of FK228 were enhanced by ASA in COX-1 positive ovarian cancer cells. In contrast, ASA had no influence on the results of FK228 treatment in COX-1 negative ovarian cancer cells. Upregulation of the cell cycle control protein p21 was induced robustly by FK228 in both cell lines. In the COX-1 positive cells, p21 expression was augmented by the addition of ASA to FK228 treatment. Furthermore, COX-1 siRNA attenuated the effects of combined ASA and FK228 on the levels of p21 expression and the amount of growth inhibition. The additional increase in p21 by ASA in FK228-treated cells was not observed at the promoter or transcriptional levels. However, a significant delay in p21 protein degradation in the presence of ASA and FK228 in COX-1 positive cells was associated with inhibition of proteasome activity. Our study provides a potential rationale for combining ASA with HDAC inhibitors in a subset of ovarian cancers.

MeSH Terms (18)

Aspirin Blotting, Western Cell Cycle Cell Line, Tumor Cell Proliferation Cyclin-Dependent Kinase Inhibitor p21 Cyclooxygenase 1 Depsipeptides Dose-Response Relationship, Drug Drug Synergism Female Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors Humans Ovarian Neoplasms Proteasome Endopeptidase Complex Reverse Transcriptase Polymerase Chain Reaction RNA Interference

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