Abstract | BACKGROUND: 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.
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Authors | Niranjan Awasthi, Changhua Zhang, Stefan Hinz, Margaret A Schwarz, Roderich E Schwarz |
Journal | Journal of experimental & clinical cancer research : CR
(J Exp Clin Cancer Res)
Vol. 32
Pg. 12
(Mar 06 2013)
ISSN: 1756-9966 [Electronic] England |
PMID | 23497499
(Publication Type: Journal Article)
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Chemical References |
- Antimetabolites, Antineoplastic
- Cytokines
- Neoplasm Proteins
- Phenylurea Compounds
- RNA-Binding Proteins
- small inducible cytokine subfamily E, member 1
- Deoxycytidine
- Niacinamide
- Sorafenib
- Gemcitabine
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Apoptosis
(drug effects)
- Carcinoma, Pancreatic Ductal
(drug therapy, metabolism, pathology)
- Cell Growth Processes
(drug effects)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Cytokines
(administration & dosage, pharmacology)
- Deoxycytidine
(analogs & derivatives, pharmacology)
- Drug Synergism
- Female
- Humans
- Mice
- Mice, SCID
- Neoplasm Proteins
(administration & dosage, pharmacology)
- Niacinamide
(administration & dosage, analogs & derivatives, pharmacology)
- Pancreatic Neoplasms
(drug therapy, metabolism, pathology)
- Phenylurea Compounds
(administration & dosage, pharmacology)
- Prognosis
- RNA-Binding Proteins
(administration & dosage, pharmacology)
- Random Allocation
- Sorafenib
- Survival Analysis
- Xenograft Model Antitumor Assays
- Gemcitabine
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