Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines.
OBJECTIVE
Gemcitabine, the first-line agent in pancreatic adenocarcinoma, has shown limited clinical benefit. Cyclooxygenase-2 (COX-2) represent one of the most promising targets for cancer prevention and treatment. In this study, we investigated whether the phytochemical curcumin, a natural COX-2 inhibitor, can potentiate gemcitabine effect on survival of human pancreatic cancer cells.


METHODS
P34 (high COX-2 expression) and Panc-1 (low COX-2 expression) pancreatic cancer cell lines were exposed to different concentrations of gemcitabine (0.1-10 microM), curcumin (0-50 microM), and their combination. Cell viability was evaluated by XTT assay. Cell cycle and apoptosis were assessed by flow cytometry. COX-2, EGFR, and p-ERK1/2 expression was measured by Western blot analysis.


RESULTS
Curcumin increased the inhibitory effect of gemcitabine on cell viability as well as its pro-apoptotic effect in COX-2 positive, p34 cells, but not in COX-2 negative, Panc-1 cells. In p34 cells, combination of curcumin and gemcitabine downregulated both COX-2 and p-ERK1/2 in a dose-dependent manner.


CONCLUSIONS
The increased cytotoxic effect of the combination on cell survival and on the induction of apoptosis in COX-2 expressing pancreatic cancer cells is probably associated with downregulation of COX-2 and p-ERK1/2 levels. This finding may contribute to the development of an effective treatment of pancreatic adenocarcinoma.
Lev-Ari
Shahar
S
Department of Oncology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Vexler
Akiva
A
Starr
Alex
A
Ashkenazy-Voghera
Maia
M
Greif
Joel
J
Aderka
Dan
D
Ben-Yosef
Rami
R
D000230:Adenocarcinoma / Q000201:enzymology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D000093542:Gemcitabine
D052246:Cyclooxygenase 2 Inhibitors; D003841:Deoxycytidine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003474:Curcumin; D000093542:Gemcitabine