Antitumor activity of the novel HDAC inhibitor CUDC-101 combined with gemcitabine in pancreatic cancer

Histone deacetylase (HDAC) is overexpressed in multiple cancers including pancreatic cancer (PC). However, the effects of histone deacetylase inhibitor (HDACi) on apoptosis and epithelial-mesenchymal transition (EMT) differ in various cancers. In this study, we aimed to investigate the anti-tumor effects of a novel multitargets HDACi, CUDC-101, combined with gemcitabine in PC cell lines. In vitro, we found that Co-treatment with CUDC-101 and gemcitabine results in greater levels of apoptosis and significantly inhibited cell proliferation on PC cells. In addition, CUDC-101 enhanced gemcitabine-induced apoptosis via inhibited PI3K/Akt/mTOR and Erk pathway activation, as indicated by the phosphorylation status of Akt, 4EBP1, S6 and Erk. We also found that co-treatment with gemcitabine and CUDC-101 not only synergistically suppressed ability of PC cell migration and invasion, but also synergistically inhibited EMT signaling pathway through modulation of cadherin, vimentin and transcription factors Snail, Slug and MMP-9. In vivo, the co-treatment group showed a significant anti-tumor function in the growth of xenograft tumors. Overall, combination of CUDC-101 and gemcitabine significantly increased anti-tumor activities compared with single drug alone, thus supporting a further evaluation of combination treatment for PC. Accordingly, it provides a rationale to investigate the combination of gemcitabine and CUDC-101 as a potential therapeutic strategy for PC.