Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and tends to be relatively resistant to conventional therapies. Activated Ras oncogene mutations are found in up to 90% of PDAC, leading to activation of the Ras/Raf/MEK/ERK signaling pathway. Sorafenib is a multikinase inhibitor of the Ras/Raf/MEK/ERK pathway and of tumor angiogenesis. Endothelial monocyte activating polypeptide II (EMAP) enhances gemcitabine effects in PDAC. Antitumor activity of sorafenib was evaluated in combination with gemcitabine (Gem) and the antiangiogenic agent EMAP in experimental PDAC.MethodsCell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival studies were performed in murine PDAC xenografts.ResultsSorafenib decreased phospho-MEK, phospho-ERK1/2, phospho-p70S6K and phospho-4EBP-1 expression in PDAC cells. Sorafenib inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on cell proliferation inhibition were observed in the gemcitabine-sorafenib combination in PDAC cells, and in combinations of sorafenib or EMAP with gemcitabine in endothelial (HUVEC) and fibroblast (WI-38) cells. Sorafenib, alone or in combination with gemcitabine and EMAP, induced apoptosis in HUVECs and WI-38 cells as observed via increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 22 days), animal survival increased after Gem therapy (29 days) but not in sorafenib (23 days) or EMAP therapy alone (25 days). Further increases in survival occurred in combination therapy groups Gem+sorafenib (30 days, p=0.004), Gem+EMAP (33 days, p=0.002), and Gem+sorafenib+EMAP (36 days, p=0.004), but not after the sorafenib+EMAP combination (24 days).ConclusionsThese findings demonstrate that the addition of a polymechanistic antiangiogenic agent such as EMAP can enhance the combination treatment effects of sorafenib and cytotoxic PDAC therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly human cancer with very poor prognosis and a 5-year survival of less than 5% [1]
Effect of sorafenib on Ras/Raf/MEK/ERK signaling Evaluation of the sorafenib effect on the Ras/Raf/MEK/ ERK signaling pathway in human PDAC cell lines revealed that 4-hour sorafenib treatment (10 μM) caused a significant decrease in the expression of phospho-MEK (Ser221), phospho-ERK1/2 (Thr202/Tyr204) and the downstream signaling proteins phospho-p70 S6 kinase (Thr389) and phospho-4E-BP1 (Thr37/46) in AsPC-1, Panc-1 and MIA PaCa-2 cells (Figure 1)
We evaluated the effect of sorafenib on phospho-p-70S6K and phospho-4E-BP1 as these proteins have recently been shown to be downstream effectors of both AKT/ mTOR and MEK/ERK signaling cascades [33]
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly human cancer with very poor prognosis and a 5-year survival of less than 5% [1] This is primarily related to its late clinical presentation, early and aggressive local or metastatic progression and high resistance to conventional chemotherapy and radiation treatments. A phase II trial of sorafenib plus gemcitabine showed no significant clinical activity in advanced PDAC [14]. These results support an evaluation of the addition of other antitumor agents to sorafenib plus gemcitabine for targeting multiple pathways that partake in PDAC progression. Antitumor activity of sorafenib was evaluated in combination with gemcitabine (Gem) and the antiangiogenic agent EMAP in experimental PDAC
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