title: Enhancing sorafenib-mediated sensitization to gemcitabine in experimental pancreatic cancer through EMAP II.
abstract: 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.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D000077157:Sorafenib; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D000093542:Gemcitabine