Synergistic activity of the histone deacetylase inhibitor trichostatin A and the proteasome inhibitor PS-341 against taxane-resistant ovarian cancer cell lines

摘要

Although a combination of platinum- and taxane-based chemotherapy is recommended for at least 70% patients with ovarian cancer as treatment subsequent to surgery, the initial response to the chemotherapy is not durable and tumors become resistant. Histone deacetylase and proteasome inhibitors are novel therapeutic agents. However, the moderate antitumoral effect of the inhibitors has restricted their clinical use when used as single agents. The aim of the present study was to investigate the synergistic activity of trichostatin A (TSA) and PS-341 in ovarian cancer cells, along with the investigation of the molecular mechanisms of taxane resistance. The taxane-sensitive ovarian cancer A2780 cell line and its resistant variant, A2780T, were treated with taxane, TSA and PS-341 at various concentrations. An Annexin V assay was performed to determine the levels of cell viability and apoptosis, while flow cytometry and immunofluorescence staining for the mitotic phase-specific protein phosphorylated-histone H3 (Ser10) were used for cell cycle detection. The effects of combined TSA and PS-341 on cell cycle-associated proteins were tested by western blot analysis. Furthermore, the present study examined the apoptosis and cell cycle arrest induced by the 3 agents subsequent to overexpression or downregulation of cyclin B1 in A2780 and A2780T cells, respectively. It was found that TSA interacted synergistically with PS-341, resulting in a marked increase in apoptosis and the rate of G2/M arrest in A2780T cells. A lower basal level of cyclin B1 expression and the incompetence of the upregulation of the cyclin may explain the taxane resistance found in A2780T cells. Collectively, the combination of TSA and PS-341 increased cyclin B1 expression level regardless of the basal expression level, resulting in the proliferation inhibition and apoptosis in A2780 and A2780T cells, which raised the possibility that a combination of the two drugs may represent a novel strategy for the treatment of ovarian cancer, particularly in taxane-resistant ovarian cancer.