Interplay Between Gemcitabine and Erlotinib Over Pancreatic Adenocarcinoma Cells.
OBJECTIVE
Pancreatic ductal adenocarcinoma remains as a chemoresistant disease with the poorest prognosis. Gemcitabine has been the standard treatment during the last decade. Erlotinib, a tyrosine kinase inhibitor, in combination with gemcitabine produces a small increase in survival. However, these results remain insufficient. The aim of this study was to investigate the molecular interplay in vitro between them regarding their effects over cytotoxicity, proliferation, apoptosis, and invasion.


METHODS
Using the human pancreatic cancer cell lines Panc-1 and BxPC-3 in vitro, the effects of gemcitabine and erlotinib therapy on growth, proliferation, and invasion were tested by cytotoxicity, cell cycle, and Annexin V-Fluorescein Isothiocyanate analysis, reverse transcription polymerase chain reaction, protein expression, and Chip assays.


RESULTS
Therapy decreased cell proliferation causing G0/G1 phase cell cycle arrest with induction of apoptosis in the Panc-1 cell line. This blockade was associated with increased p27 expression. Besides, treatments enhanced the nuclear factor-κB (NF-κB) pathway and the binding of NF-κB to the promoters of genes related to the proliferation and the evasion of apoptosis.


CONCLUSIONS
Our data suggest that, although gemcitabine and erlotinib exert antiproliferative effects over pancreatic cancer cell lines, the gemcitabine-induced activation of NF-κB expression and its DNA-binding activities are important drawbacks of this treatment against pancreatic cancer.
From the *Department of Biochemistry and Molecular Biology I, University of Granada; and †Oncology Service, Virgen de las Nieves Hospital, Granada, Spain.
Carolina
C
Torres
Ana
A
Linares
Maria Jose
MJ
Alejandre
Rogelio Jesus
RJ
Palomino-Morales
Juan Ramon
JR
Delgado
Sonia
S
Perales
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D016328:NF-kappa B; D003841:Deoxycytidine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine