Abstract
BackgroundSuberoylanilide hydroxamic acid (SAHA) is a member of the hydroxamic acid class of the newly developed histone deacetylase inhibitors. Recently, Suberoylanilide hydroxamic acid has attracted increasing attention because of its antitumor activity and synergistic effects in combination with a variety of traditional chemotherapeutic drugs. Paclitaxel (PTX), is a natural anticancer drugs; however, resistance to paclitaxel has become a major challenge to the efficacy of this agent. The purpose of this study was to investigate the effects of the combined application of these two drugs on the paclitaxel-resistant ovarian cancer OC3/P cell line.MethodsIn the present study, the effects of Suberoylanilide hydroxamic acid or/and paclitaxel on OC3/P cells cultured in vitro were analyzed in terms of cell viability, migration, cell-cycle progression and apoptosis by CCK-8, wound healing and flow cytometry assays. Changes in cell ultrastructure were observed by transmission electron microscopy. The expression of genes and proteins related to proliferation, apoptosis and drug resistance were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses.ResultsThere was no cross-resistance of the paclitaxel-resistant ovarian cancer OC3/P cells to Suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid combined with paclitaxel significantly inhibited cell growth and reduced the migration of OC3/P cells compared with the effects of Suberoylanilide hydroxamic acid or paclitaxel alone. Q-PCR showed the combination of Suberoylanilide hydroxamic acid and paclitaxel reduced intracellular bcl-2 and c-myc gene expression and increased bax gene expression more distinctly than the application of SAHA or paclitaxel alone. Moreover, the level of mdr1 gene expression in cells treated with Suberoylanilide hydroxamic acid was lower than that of the control group (P <0.05). Western blot analysis showed that Suberoylanilide hydroxamic acid alone or in combination with paclitaxel enhanced caspase-3 protein expression and degraded ID1 protein expression in OC3/P cells.ConclusionSuberoylanilide hydroxamic acid inhibited the growth of paclitaxel-resistant ovarian cancer OC3/P cells and reduced migration by the induction of cell-cycle arrest, apoptosis and autophagy. These observations indicate the possible synergistic antitumor effects of sequential Suberoylanilide hydroxamic acid and paclitaxel treatment.
Highlights
Suberoylanilide hydroxamic acid (SAHA) is a member of the hydroxamic acid class of the newly developed histone deacetylase inhibitors
SAHA has been shown to inhibit the survival of sensitive ovarian cancer, and to have synergistic effects in combination with decitabine and paclitaxel [18,19,20,21,22,23]
Our study showed that SAHA inhibited the growth of Paclitaxel-sensitive ovarian cancer cell line (OC3)/P cells and reduced migration by the induction of cell-cycle arrest, apoptosis and autophagy
Summary
Suberoylanilide hydroxamic acid (SAHA) is a member of the hydroxamic acid class of the newly developed histone deacetylase inhibitors. Suberoylanilide hydroxamic acid has attracted increasing attention because of its antitumor activity and synergistic effects in combination with a variety of traditional chemotherapeutic drugs. Suberoylanilide hydroxamic acid (SAHA) is a HDACI that shows strong anti-proliferative effects on various cancer cell lines and is currently in clinical trials for the treatment of certain solid and hematological tumors [12,13,14,15]. SAHA has been shown to inhibit the survival of sensitive ovarian cancer, and to have synergistic effects in combination with decitabine and paclitaxel [18,19,20,21,22,23]. There are currently no reports of systematic studies on the mechanism of the effects mediated by SAHA, alone and in combination with PTX, on paclitaxel-resistant ovarian cancer cell lines
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