Abstract
BackgroundIn most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC.MethodsThe effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured.ResultsPanobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment.ConclusionsPanobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was equal in the orthotopic EOC model used. We conclude that panobinostat is a promising therapeutic alternative that needs to be further assessed for the treatment of EOC.
Highlights
Epithelial ovarian cancer (EOC) is the sixth most common malignant neoplasm in women worldwide, and the seventh most common cause of cancer death [1]
The efficacy of panobinostat and carboplatin was equal in the orthotopic epithelial ovarian carcinomas (EOC) model used
We conclude that panobinostat is a promising therapeutic alternative that needs to be further assessed for the treatment of EOC
Summary
Epithelial ovarian cancer (EOC) is the sixth most common malignant neoplasm in women worldwide, and the seventh most common cause of cancer death [1]. The overall five-year survival rate is still below 45% [6]. Over the last 10 years, a large number of phase II and III studies have evaluated multidrug combinations, dose-dense scheduling, intraperitoneal delivery routes and maintenance therapy, as well as targeting of angiogenesis and poly/ADP-ribose polymerase (PARP) with marginal or no improvement in overall survival [7,8,9,10,11]. In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. We wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC
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