The underlying mechanisms and the consequences of RelA p65 acetylation and deacetylation cant be clarified completely Fluoro-Sorafenib within the scope of this translational work. This should be done in future functional studies. One pos sible mechanism by which RelA p65 could be inhibited by HDIs might be the loss of I B phosphorylation, which we observe in our in vitro experiments and which should lead to an enhanced I B accumulation and sequestering of RelA p65 in the cytoplasm. to pancreatic carcinogenesis. Furthermore, conven tional chemotherapeutics like gemcitabine or paclitaxel are often associated with high resistance rates in pancre atic neoplasms, which is partly due to a constitutively acti vated RelA NF B pathway. A combinational treatment with HDIs which are able to inhibit RelA p65 activity might be of use to overcome such resistances.

Conclusion In conclusion, we demonstrated that class I HDACs are overexpressed in pancreatic cancer and that high class I HDAC expression is significantly correlated to nuclear translocation of the transcription factor RelA p65 in pan creatic adenocarcinoma. The close relationship of class I HDACs and RelA p65 was confirmed in vitro, where nuclear translocation and binding activity of RelA p65 could be markedly diminished by treatment of pancreatic cancer cells with HDAC inhibitors. Our data support the assumption that treatment with HDAC inhibitors, either as single agents or in combina tion with other chemotherapeutics, could serve as a potential approach in the targeted therapy of pancreatic carcinoma.

Background An underlying feature of all human cancer is uncon trolled cell proliferation. However, for a tumor to increase in cell mass and malignant potential, the increase in replication rate must be accompanied by suppression of apoptosis. While tumor cells can sub vert many apoptotic regulators, the anti apoptotic IAP family is thought to have a central role in this process. There are eight IAPs in humans. All IAPs contain multiple functional domains that potentially modulate many biological processes, including apoptosis. For instance, IAPs have a role in cell cycle regulation through mitotic Entinostat spindle formation, ubiquitination of tar get proteins, and modulation of several signal transduc tion pathways. Elevated IAP protein levels are common in many tumor types, and a wealth of data supports their role in suppressing cell death, although the exact mechanisms by which different IAPs mediate this effect remains unclear XIAP is the most thoroughly characterized of this family, and is the only member that can directly inhibit the proteolytic activity of caspases in vitro. Caspase inhibition is mediated through an 80 amino acid motif, the Baculovirus IAP Repeat domain, common to all IAPs.