Synergistic cytotoxicity and molecular interaction on drug targets of sorafenib and gemcitabine in human pancreas cancer cells.
BACKGROUND
Current treatments have a modest impact on survival of pancreatic cancer patients and this study investigates the interaction between sorafenib and gemcitabine and the molecular pharmacodynamics of this combination.


METHODS
The pancreatic cancer cells were treated with sorafenib and gemcitabine, alone or in combination. The effects of treatments were evaluated on cell proliferation, cell cycle, apoptosis, phosphorylation of Akt, c-Kit, ERK and VEGFR2, and expression of genes related to drug activity.


RESULTS
Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation, and assessment of apoptosis demonstrated that drug associations increased the apoptotic index. Sorafenib reduced c-Kit, ERK and VEGFR2 activation and on the other hand, gemcitabine inhibited Akt phosphorylation. Moreover, quantitative PCR showed that sorafenib modulated the expression of genes related to gemcitabine activity, while gemcitabine induced the expression of RKIP.


CONCLUSIONS
These data demonstrate that gemcitabine and sorafenib combination displays a synergistic effect in pancreatic cancer cells.
Ricciardi
Simona
S
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy. simonaricciardi@gmail.com
Mey
Valentina
V
Nannizzi
Sara
S
Pasqualetti
Giuseppe
G
Crea
Francesco
F
Del Tacca
Mario
M
Danesi
Romano
R
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000093542:Gemcitabine