title: Effects of suberoylanilide hydroxamic acid (SAHA) combined with paclitaxel (PTX) on paclitaxel-resistant ovarian cancer cells and insights into the underlying mechanisms.
abstract: BACKGROUND
  Suberoylanilide 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  There 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.
  
  
  CONCLUSIONS
  Suberoylanilide 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.
authors.affiliation: Department of Obstetrics and Gynecology, Air Force General Hospital, Beijing, 100142 China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Air Force General Hospital, Beijing, 100142 China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing, 100850 China.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Air Force General Hospital, Beijing, 100142 China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Air Force General Hospital, Beijing, 100142 China.
authors.forename: Chundong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Air Force General Hospital, Beijing, 100142 China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing, 100850 China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
keywords: Antitumor; Apoptosis; Cell-cycle arrest; Chemotherapy; Histone deacetylase inhibitors; Paclitaxel; Resistance; Suberoylanilide hydroxamic acid; Synergistic