The epigenetic agents suberoylanilide hydroxamic acid and 5-AZA-2′ deoxycytidine decrease cell proliferation, induce cell death and delay the growth of MiaPaCa2 pancreatic cancer cells in vivo

Abstract

Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5-year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic therapeutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5-AZA-2′ deoxycytidine (5-AZA-dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5-AZA-dc, resulted in higher cell death and lower DNA synthesis compared to 5-AZA-dc alone and controls (DMSO). Further, combination treatment with SAHA and 5-AZA-dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents.