Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells

Abstract

Histone deacetylase inhibitors (HDACis) are antineoplastic agents that affect cell growth, differentiation and invasion in a variety of different cancer types, although the underlying mechanisms have not been completely clarified yet. In this study, we compared the effects of two HDACis, namely Trichostatin A (TSA) and Valproic Acid (VPA) in the induction of both cell death and autophagy in the pancreatic cancer cell lines PaCa44 and Panc1. These cells are characterized by a high metastatic capacity and display k-RAS/p53 double mutation. We found that both HDACis reduced cell survival and induced pancreatic cancer cells apoptosis by triggering mitochondrial membrane depolarization, cytochrome C release and caspase 3 activation, although VPA was more effective than TSA, especially in Panc1. Among the underlying molecular mechanism/s leading to the HDACis-mediated cytotoxic effect, we found that ERK1/2 was de-phosphorylated and c-Myc and mutant p53 protein levels were reduced by VPA and to a lesser extent by TSA. Up-regulation of p21 and Puma was also observed, suggesting a possible wild-type p53 re-activation, concomitantly with mutant p53 degradation. In addition, in both cell lines VPA increased the pro-apoptotic Bim, reduced the anti-apoptotic Mcl-1, induced ROS production and autophagy while TSA was able to mediate these effects only in PaCA44 cells. These results suggest that VPA, that specifically inhibits class I HDAC, may have a stronger and broader cytotoxic effect in comparison with TSA against pancreatic cancer and could represent a better choice in pancreatic anticancer therapy, alone or in combination with other drugs.