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

Abstract

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 anti-tumor agents. However, it remains unclear which anti-tumor 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.

Synergistic Effects of Exemestane and Aspirin on MCF-7 Human Breast Cancer Cells

“…Our data demonstrated that the combination treatment caused a large relative decrease in the expression of COX-1 and PGE2 as compared to in the control or single-agent treatment.Wheras the expression levels of COX-2 was not altered in response to exemestane, aspirin alone, or the combination. Some preclinical studies have also shown that COX-1 selective inhibition exhibited significant inhibitory effects in bladder cancer cells in vitro (Mohseni et al, 2004), ovarian cancer cell lines (Daikoku et al, 2005;Daikoku et al, 2006;Son et al, 2010) and human breast cancer (Connolly et al, 2002;Kundu and Fulton 2002;Ristimaki et al, 2002;McFadden et al, 2006;Howe 2007). These data suggest that COX-1 may play an important role of the anticancer activity in our study.…”

“…In the present study,we investigated that aspirin exhibited remarkably anti-proliferative effects and dose dependent growth inhibition on MCF-7 human breast cancer cells. Some preclinical studies have shown that aspirin synergistically enhanced the anti-tumor effect of chemotherapy in ovarian cancer and colon cancer (Kanthamneni et al, 2010;Son et al, 2010).…”

Romidepsin (FK228) combined with cisplatin stimulates DNA damage-induced cell death in ovarian cancer

“…Our group and others have shown that nanomolar concentrations of FK228 effectively reduce cell viability in ovarian cancer cells [5, 11, 21, 22]. Here, we evaluated the anti-proliferative and cytotoxic effects of FK228 (1– 10 nM), cisplatin (0.5–5 μM) and the combination by conducting SRB cellular assays 72 h after drug exposure (Fig 1A).…”

Combined histone deacetylase and cyclooxygenase inhibition achieves enhanced antiangiogenic effects in lung cancer cells

“…HDACI have shown preclinical efficacy in solid tumors, including ovarian cancers. A recent study reported that the combined treatment of the HDACI and COXs inhibitor showed enhanced anti tumor effects in ovarian cancer cells [29]. …”