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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. Aim: 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 µM of nimesulide suppressed COX-2 enzyme activity because of reduced PGE2 production, and then induced growth inhibition and cell apoptosis despite no alterations of COX-2 protein expression. Importantly, the combination of 50 µM or 100 µM of nimesulide and low concentrations (5 µM to 20 µM) of doxorubicin resulted in enhanced cell growth inhibition, apoptosis induction and reduced VEGF production. Conclusion: 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.
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