Schedule-dependent Effect and Apoptotic Potential of a Cyclooxygenase-2 Selective Inhibitor Etodolac plus 5-fluorouracil-induced Cytotoxicity in Human Liver Tumor Cells

• Main Authors: Tzu-Chih Hsiao, 蕭自智
• Other Authors: Robert Y. Peng
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/40800998117515920318

碩士 === 弘光科技大學 === 生物科技研究所 === 94 === Introduction and purpose : Recent studies have demonstrated that cyclooxygenase-2 (COX-2) plays a crucial role in tumorigenesis, COX-2 is usually cited to be involved in tumorigenesis of cancer. As well known to all, the evaluation of synergistic effects is one of the most issue in pharmacological studies. Especially, in cancer therapy, most chemotherapeutic agents are administered with a single or two other drugs with the aim to reduce the drug resistance, side effects and to increase the tumor suppresive rate. The aim of this study was to investigate whether the selective COX-2 inhibitors (e.x., etodolac) exert anti-proliferative effect in hepatocellular cancer cell lines Hep G2 and HA22T and may be used in combination with the conventional chemotherapeutic drugs 5-FU for the treatment of hepatocellular cancer cell lines, the latter effect is possibly mediated via enhancement of apoptosis. Thus we investigated the interactive effects of a selective COX-2 inhibitor, etodolac, in combination with 5-FU in hepatocellular cancer cell lines, in simultaneous or sequential administration schedules. Materials and Methods : Hepatocellular cancer cell lines of Hep G2, HA22T and KEL FIB cell lines were cultured. The selective COX-2 inhibitor etodolac, 5-FU, or etodolac combined with 5-FU were added to the cultures and co-cultured for 48 hours respectively. Cell proliferation and apoptosis rate were observed with MTT assay and flow cytometry. Results : Both etodolac and 5-FU inhibited growth of hepatocellular cancer cell lines and KEL FIB cell line in a dose-dependent and time-dependent manners. The apoptotic activity induced by etodolac in combination with 5-FU was more effective than etodolac or 5-FU alone as evidenced by the cell death of hepatocellular cancer cell lines. Furthermore, the apoptotic rate induced by etodolac in combination with 5-FU was significantly increased compared to that by sequential exposure to etodolac then to 5-FU or 5-FU then followed by etodolac. Conclusion : Etodolac, a selective COX-2 inhibitor can be used as a subsidiary drug in 5-FU chemotherapy for treating hepatocellular cancer cell lines. In our study, we have demonstrated that the cytotoxic effect of etodolac, based on the induction of apoptosis and inhibition of proliferation and differention, in combination with 5-FU was schedule-dependent, which is actually favoring a simultaneous administration. These findings provide a preclinic experiment basis for a combinatorial therapy using etodolac and 5-FU in treatment of human hepatocellular carcinoma.