Combination of cyclooxygenase-2 inhibitor and doxorubicin increases the growth inhibition and apoptosis in human hepatocellular carcinoma cells.
Inhibition of cyclooxygenase (COX)-2 elicits therapeutic effects in solid tumors that are coupled with the inhibition of cell proliferation and induction of apoptosis in tumor cells.


OBJECTIVE
This study was designed to investigate the role of COX-2 inhibitor nimesulide in cell growth and apoptosis of the cultured human hepatocellular carcinoma HepG2 cells.


METHODS
We performed the MTT assay, flow cytometric analysis and cell morphology study to evaluate growth inhibition and cell apoptosis upon the action of nimesulide alone or along with doxorubicin, a common agent for the treatment of human hepatocellular carcinoma.


RESULTS
Our results showed that the treatment of HepG2 cells with more than 50 microM of nimesulide suppressed COX-2 enzyme activity because of reduced PGE(2) production, and then induced growth inhibition and cell apoptosis despite no alterations of COX-2 protein expression. Importantly, the combination of 50 microM or 100 microM of nimesulide and low concentrations (5 microM to 20 microM) of doxorubicin resulted in enhanced cell growth inhibition, apoptosis induction and reduced VEGF production.


CONCLUSIONS
These data suggest synergistic and/or additive effects of COX-2 inhibitors and chemotherapeutic agents, and may provide the rational for clinical studies of COX-2 inhibitors on the treatment or chemoprevention of human hepatocellular carcinoma.
Pan
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YY
Institute of Clinical Pharmacology of Anhui Medical University, Key Laboratory of Antiinflammatory and Immunological Pharmacology in Anhui Province, Anhui Medical University, China. yueyinpan@gmail.com
Xu
S P
SP
Jia
X Y
XY
Xu
H Q
HQ
Zhang
Y
Y
Rui
L X
LX
Wei
W
W
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004338:Drug Combinations; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D008565:Membrane Proteins; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C012655:nimesulide