植化素抑制大腸直腸癌中indoleamine-2,3-dioxygenase活性之探討

林育如

doi:10.6342/NTU.2013.02829

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植化素抑制大肠直肠癌中indoleamine-2,3-dioxygenase活性之探讨

Inhibition effects of phytochemicals on indoleamine-2,3-dioxygenase activity in colorectal cancer

林育如 , 硕士　　导师：蒋丙煌　　

繁体中文 DOI： 10.6342/NTU.2013.02829

大肠直肠癌； Indoleamine-2,3-dioxygenase ；植化素； Tryptophan-2,3-dioxygenase ； Colorectal cancer ； indoleamine-2,3-dioxygenase ； phytochemicals ； Tryptophan-2,3-dioxygenase

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Tumor cells display multiple immunosuppressive mechanisms against the host immune system. One of the tumor immunosuppression mechanisms involves the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). IDO degrades tryptophan which results tryptophan starvation of local environment. Tryptophan starvation and the proapoptotic tryptophan catabolites, kynurenine, consequently inhibit T cell response and proliferation. Recent studies indicated that many tumor cells constantly express IDO which enable tumor cells to avoid immune attack of T cells. In several colorectal cancer case studies, it has been proposed that high-IDO expression was associated with significantly low T cells, which may correlate to poor prognosis and liver metastasis. Phytochemicals are chemical compounds that occur naturally in plants and have been reported to have antitumor activity. According to recent studies, some of the phytochemicals have ability to inhibit IDO activity in cancer cells. The aim of this research was to use colonrectal cancer cell lines to identify the phytochemicals which have anti-IDO effects on colorectal cancer.
We first prepared two colorectal cancer cell lines, LoVo and HCT116, and used them as IDO-expressing cell models. We found that these two cell lines express IDO mRNA by the induction of interferon-γ (IFN-γ). In addition, IFN-γ decreased tryptophan and increased kynurenine concentratins in the culture medium.We further found that LoVo cells expressed tryptophan-2,3-dioxygenase (TDO) mRNA. In our human colon polyp ex vivo study, it showed that IDO mRNA was also induced by IFN-γ stimulation. In the second part of our research, we tested 9 phytochemicals including EGCG, curcumin, resveratrol, quercetin, sulforaphane, 6-shogaol, diallyl trisulfide (DATS), brassinin andits derivate 5-br-brassinin, to see if they were able to inhibit colorectal cancer cells to convert tryptophan to kynurenine. Results showed that EGCG, 6-shogaol, brassinin, 5-br-brassinin, sulforaphane, DATS were able to inhibit both LoVo and HCT116 cells to release kynurenine into cell medium. In the third part, we investigated the inhibition mechanism of EGCG and DATS. Results indicated that EGCG showed IDO and TDO mRNA inhibiting activity. However, DATS did not show inhibition effect on IDO or TDO gene expression. The mechanism of how DATS inhibits IDO activity in colorectal cancer cells is still unclear and needs further study.

参考文献 ( 111 ) 〈TOP〉

吴哲诚。以Wnt/β-catenin讯息路径探讨姜中活性成份对於大肠直肠癌预防功效与机转之研究。国立台湾大学食品科技研究所硕士论文。2011。
连结：
Adachi, S.; Shimizu, M.; Shirakami, Y.; Yamauchi, J.; Natsume, H.; Matsushima-Nishiwaki, R.; To, S.; Weinstein, I. B.; Moriwaki, H.; Kozawa, O. (-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells. Carcinogenesis 2009, 30, 1544-1552.
连结：
Aggarwal, B. B.; Bhardwaj, A.; Aggarwal, R. S.; Seeram, N. P.; Shishodia, S.; Takada, Y. Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies. Anticancer Res. 2004, 24, 2783-2840.
连结：
Ahmad, N.; Gupta, S.; Mukhtar, H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. Arch. Biochem. Biophys. 2000, 376, 338-346.
连结：
Banerjee, T.; DuHadaway, J. B.; Gaspari, P.; Sutanto-Ward, E.; Munn, D. H.; Mellor, A. L.; Malachowski, W. P.; Prendergast, G. C.; Muller, A. J. A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene 2007, 27, 2851-2857.
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DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。