Argyrin F therapy attenuates carcinogensis of pancreatic adenocarcinoma (PDAC)

Abstract

PDAC is the fourth most common cause of cancer death in the US and Europe. Current systemic chemotherapies are limited and new drugs are needed to improve survival. In the present study, we have analyzed in vitro (KP3, Panc-1) and in vivo (Pdx1-Cre; LSL-KrasG12D; p53 lox/+) the antitumor effect of the proteasome inhibitor Argyrin F (AF) single and in combination with Gemcitabine (AF+G). In vitro, AF therapy induced a dose-and time-dependent growth inhibition of KP3 and Panc-1 cells. Moreover, AF treatment resulted in an inhibition of migration, invasion and colony formation in PDAC cell lines. AF therapy induced a considerable amount of apoptosis and partially senescence in the tested PDAC cell lines in a dose-and time-dependent manner. Furthermore, cell cycle profile analysis showed that AF induced a gradually increasing population of cells in sub-G1-phase for KP3 cells and also resulted in a G1/S-phase arrest on Panc-1 cell. AF treatment showed considerable inhibition of EMT in Panc-1 cells but not in KP3 cells. In vivo, most importantly, combinational treatment by AF+G showed prolonged survival and caused significant tumor reduction. Less incidences of metastasis and ascites was observed after AF single and AF+G treatment. Expression of both the markers ki67 and CD34 showed reduced expression in the treament groups (AF, AF+G). AF and AF+G treatment regimes were well tolerated by all the animals used in the study. In conclusion, our work demonstrates that treatment with AF can successfully inhibit the growth of PDAC in vitro and in vivo. Especially, AF in combination with G might be a new and promising therapeutic approach for patients with PDAC, but further studies are needed to validate our findings.