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Introduction: Pancreatic cancer is one of the most lethal human malignancies with five-year survival of less than 5 % because of its resistance to most conventional chemotherapies like gemcitabine and other novel anti-cancer therapies like TRAIL. Histone deacetylase (HDAC) inhibitors are a new and promising drug family with strong anticancer activity. The aim of the current study was to evaluate whether inhibition of histone deacetylase sensitizes pancreatic cancer to TRAIL induced cell death.
Methods: Highly aggressive metastatic pancreatic cancer cell lines (S2VP10, Capan-1) were treated with the HDAC inhibitor, Vorinostat (0-5µM), TRAIL (0-40ng/ml) or a combination of Vorinostat and TRAIL for 12-72h. The effect on cell viability was evaluated using a WST-8 cell viability assay (Dojindo Labs), apoptosis (caspase 3, 8 and 9 activation) was evaluated using Caspase Glo assay kit (Promega).
Results: HDAC inhibition markedly increased TRAIL induced cell death in both pancreatic cancer cell lines evaluated. Viability, data expressed as % of Control (untreated cells), mean ±SEM. S2VP10 (48h): Vorinostat (5µM) - 64.5 ± 0.1%, TRAIL (20 ng/ml) - 95.13±0.825%, Vorinostat (5µM) + TRAIL (20ng/ml) - 41±0.8%. HDAC inhibition markedly augmented Caspase 3 activation in response to TRAIL. Caspase 3, data expressed as % of Control, mean ±SEM. S2VP10 24h: Vorinostat (5µM) - 206.1±12.07%, TRAIL (20 ng/ml) - 159.6±1.2%, Vorinostat (5µM) + TRAIL (20ng/ml) - 2187.4±77.62%.
Conclusion: Inhibition of Histone deacetylases sensitizes pancreatic cancer cells to TRAIL induced apoptosis and cell death. Combination of HDAC inhibition and TRAIL has immense potential to emerge as novel therapeutic strategy against pancreatic cancer.