Abstract
BackgroundIn most patients with ovarian cancer, diagnosis occurs after the tumour has disseminated beyond the ovaries. In these cases, post-surgical taxane/platinum combination chemotherapy is the "gold standard". However, most of the patients experience disease relapse and eventually die due to the emergence of chemotherapy resistance. Histone deacetylase inhibitors are novel anticancer agents that hold promise to improve patient outcome.MethodsWe compared a prototypic histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), and paclitaxel for their treatment efficacy in ovarian cancer cell lines and in primary patient-derived ovarian cancer cells. The primary cancer cells were isolated from malignant ascites collected from five patients with stage III ovarian carcinomas. Cytotoxic activities were evaluated by Alamar Blue assay and by caspase-3 activation. The ability of SAHA to kill drug-resistant 2780AD cells was also assessed.ResultsBy employing the cell lines OVCAR-3, SK-OV-3, and A2780, we established SAHA at concentrations of 1 to 20 μM to be as efficient in inducing cell death as paclitaxel at concentrations of 3 to 300 nM. Consequently, we treated the patient-derived cancer cells with these doses of the drugs. All five isolates were sensitive to SAHA, with cell killing ranging from 21% to 63% after a 72-h exposure to 20 μM SAHA, while four of them were resistant to paclitaxel (i.e., <10% cell death at 300 nM paclitaxel for 72 hours). Likewise, treatment with SAHA led to an increase in caspase-3 activity in all five isolates, whereas treatment with paclitaxel had no effect on caspase-3 activity in three of them. 2780AD cells were responsive to SAHA but resistant to paclitaxel.ConclusionThese ex vivo findings raise the possibility that SAHA may prove effective in the treatment of paclitaxel-resistant ovarian cancer in vivo.
Highlights
In most patients with ovarian cancer, diagnosis occurs after the tumour has disseminated beyond the ovaries
The standard treatment is a combination of surgery and chemotherapy, the latter usually consisting of a taxane/platinum combination
Comparison of the cytotoxic activities of suberoylanilide hydroxamic acid (SAHA) and paclitaxel on ovarian cancer cells Initially, we compared the cytotoxic activities of SAHA and paclitaxel by employing the ovarian carcinoma cell lines OVCAR-3, SK-OV-3, and A2780
Summary
In most patients with ovarian cancer, diagnosis occurs after the tumour has disseminated beyond the ovaries. In these cases, post-surgical taxane/platinum combination chemotherapy is the "gold standard". The standard treatment is a combination of surgery and chemotherapy, the latter usually consisting of a taxane/platinum combination. By this regimen, initial response rates of more than 80% are achieved [2]. In the vast majority of women, diagnosis occurs after the disease has already disseminated beyond the ovaries These patients typically relapse and eventually die as the tumours become refractory to treatment. Novel treatment strategies to overcome drug resistance, are urgently needed
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