Specifically for this reason, antiendothelial and antiangiogenic agents may be beneficial in combination therapy approaches for PDAC treatment. In the present study we evaluated the antitumor activity of sorafenib, and the enhancement of gemcitabine response by addition of sorafenib and the antiangiogenic agent EMAP in experimental pancreatic cancer. We demonstrate that in PDAC cells sorafenib

treatment effectively blocked phosphorylation of MEK (Ser221), ERK1/2 (Thr202/Tyr204) and downstream target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46) in most of the cell lines tested except BxPC-3, where upstream MEK and ERK phosphorylation was inhibited but not the downstream signaling proteins

VX-680 p70S6K or 4-EBP-1. These findings suggest that sorafenib may cause some specific effects that result in blockage of Ras/Raf/MEK/ERK signaling and interfere with pancreatic cancer cell proliferation, differentiation and survival. Sorafenib treatment decreased cell proliferation and induced apoptosis in ECs and fibroblasts indicating that the in vivo antitumor effects of sorafenib may be due to its direct cytotoxic effects on various tumor TGF-beta assay cellular components, in addition to its antiangiogenic properties. Previous studies have shown marked heterogeneity in gemcitabine and other chemotherapeutic agent response Erismodegib price towards PADC cells [38–40]. We also observed a heterogeneous response of sorafenib and gemcitabine in inhibiting cell proliferation ADP ribosylation factor of four PDAC lines tested. Both agents caused inhibition of cell proliferation to different extents and the addition of sorafenib improved gemcitabine effects. Effects

of combinations of EMAP with sorafenib and gemcitabine were evaluated in ECs and fibroblast cells, and a significant additive effect on inhibition of cell proliferation was observed compared with single or dual agent treatment. A gemcitabine plus sorafenib combination was found to be effective in preclinical and phase I trials of PDAC, lending support to the importance of combining cytotoxic drugs with agents inhibiting Ras/Raf/MEK/ERK pathways and angiogenesis [9–11, 13]. However, a phase II trial showed no meaningful effect of the gemcitabine plus sorafenib combination in advanced PDAC patients [14]. The very small number of 17 patients and 94% of patients carrying metastatic disease were the contributing factors in the negative phase II clinical trial results [14]. These results also indicate the importance of targeting other relevant pathways that contribute in the progression of PDAC. Currently, two phase II trials are evaluating the combination treatment benefits of gemcitabine, sorafenib and the EGFR inhibitor erlotinib in advanced PDAC.