Quercetin合併irinotecan/SN-38對人類胃癌細胞增生及轉移相關因子之影響：體內及體外實驗

Effects of quercetin combined with irinotecan/SN-38 on proliferation and metastasis-associated factors of human gastric cancer cells: in vivo and in vitro studies

雷慶萱(Cing-Syuan Lei)

指導教授 ： 葉松鈴

臺北醫學大學/公共衛生暨營養學院/保健營養學研究所/碩士(2015年)

摘要

化學治療對於大多數胃癌病人來說仍然是重要的，irinotecan (CPT-11)為胃癌之第一線化療藥物，其屬於DNA topoisomerase I抑制劑。然而，病人對於單一化療藥物之反應率(response rate)較低，數種化療藥物合併使用雖能提高反應率，但卻不一定會延長病人之存活時間，這些都是胃癌化療所面臨的挑戰。槲皮素(quercetin)為廣泛存在於蔬菜水果中的類黃酮物質，其對於某些抗癌藥物之效能具有加強效果，因此，本研究透過細胞與動物實驗，探討合併quercetin與irinotecan/SN-38 (活化型態之irinotecan)對於人類胃癌細胞株AGS之治療效果。從細胞實驗結果發現，合併給予quercetin及SN-38的組別與單獨給予SN-38的組別相比，其細胞存活率及細胞凋亡比例沒有顯著差異。在AGS異種移植小鼠模式中發現，血液循環內皮前趨細胞(circulating endothelial progenitors, CEPs)的比例在各組間沒有顯著差異，而合併給予quercetin及irinotecan的組別，其血液中循環內皮細胞(circulating endothelial cells, CECs)的比例高於單獨給予irinotecan的組別；腫瘤組織中Tie2的單核球細胞(Tie2-expressing monocytes, TEMs)之比例在單獨給予irinotecan的組別顯著上升，而合併給予quercetin及irinotecan的組別則對TEMs有負向調節的作用；此外，腫瘤組織中 COX-2、TGF-β 及EMT相關分子 (ITGβ6和vimentin) 之基因表現量在合併給予quercetin及irinotecan的組別皆顯著低於單獨給予irinotecan的組別。總結來說，本研究結果顯示，quercetin有助於提升irinotecan及SN-38在人類胃癌細胞AGS 中的作用效果。

關鍵字

胃癌 ； 槲皮素 ； Irinotecan ； SN-38 ； 循環內皮細胞 ； 上皮間質轉化

並列摘要

Chemotherapy is essential to most of the patients with gastric cancer and irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, is the first-line chemotherapy for gastric cancer. However, low response rates in patients to single-agent chemo and unimproved survival rates in patients to multi-agent chemo are major challenges in chemotherapy of gastric cancer. Quercetin, a flavonoid that can be easily found in various vegetables and fruits, has ability to potentiate the efficacy of anti-cancer drugs. The purpose of this study is to investigate the therapeutic effect of quercetin combined with irinotecan/SN-38 (active form of irinotecan) in human gastric cancer cell line AGS in vitro and in vivo. Results from in vitro studies indicated that cell viability and percentage of apoptosis in combined treatments with quercetin and SN-38 were comparable to the treatment with SN-38 alone. In the AGS xenograft mouse model, there were no significant differences in the percentage of CEPs among groups. CECs population in combined treatments with quercetin and irinotecan was higher than irinotecan alone. The percentage of TEMs in irinotecan alone was significantly elevated whereas the TEMs population was down-regulated in combined treatments with quercetin and irinotecan. Furthermore, the gene expression of COX-2, TGF-β and some EMT-related markers (ITGβ6 and vimentin) were lower in combined treatments with quercetin and irinotecan than irinotecan alone. In summary, this study indicated quercetin may enhance the efficacy of irinotecan/SN-38 in human gastric adenocarcinoma cell line AGS.

並列關鍵字

Gastric cancer ； Quercetin ； Irinotecan ； SN-38 ； Circulating endothelial cells (CEC) ； Epithelial-mesenchymal transition (EMT)

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