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Enhancing sorafenib-mediated sensitization to gemcitabine in experimental pancreatic cancer through EMAP II
Niranjan Awasthi1, Changhua Zhang, Stefan Hinz
1Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Background:
Pancreatic 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.
Methods:
Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival studies were performed in murine PDAC xenografts.
Results:
Sorafenib 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).
Conclusions:
These 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.
Insights
Combining sorafenib, gemcitabine, and EMAP significantly improved survival in pancreatic cancer models. This triple therapy offers a promising strategy for treating pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options.
- Ras oncogene mutations activate the Ras/Raf/MEK/ERK pathway, common in PDAC.
- Sorafenib targets this pathway and tumor angiogenesis; EMAP enhances gemcitabine efficacy.
Purpose of the Study:
- To evaluate the antitumor activity of sorafenib in combination with gemcitabine (Gem) and EMAP in experimental PDAC.
- To assess the impact of these combinations on cell proliferation, protein expression, and animal survival.
Main Methods:
- Cell proliferation assessed by WST-1 assay; protein expression by Western blotting.
- Animal survival studies conducted using murine PDAC xenografts.
- Apoptosis analyzed via cleaved PARP-1 and caspase-3 expression.
Main Results:
- Sorafenib reduced proliferation and key signaling proteins (p-MEK, p-ERK) in PDAC cells.
- Combinations of Gem with sorafenib or EMAP showed additive effects on proliferation inhibition.
- Triple therapy (Gem+sorafenib+EMAP) significantly increased median survival in mice (36 days) compared to controls (22 days).
Conclusions:
- The combination of sorafenib and gemcitabine demonstrates additive effects in PDAC treatment.
- Adding EMAP, a polymechanistic antiangiogenic agent, enhances the combined effects of sorafenib and gemcitabine.
- This study supports EMAP as a valuable addition to sorafenib and cytotoxic PDAC therapy.
