新穎HDAC抑制劑在結腸炎及大腸直腸癌幹細胞之研究

Effects of a novel HDAC inhibitor on colitis and colorectal cancer stem cells

林怡亭(Yi-Ting Lin)

指導教授 ： 陳青周

國立臺灣大學/醫學院/藥理學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.2012.03419

摘要

發炎性腸道疾病 (IBD) 為一慢性疾病，尚未有治癒之藥物，僅能使症狀獲得控制與緩解，腸道長期處於發炎狀態易導致併發症並增加罹癌風險，長期發炎導致之癌症可能是源於癌幹細胞。JMF-1為statin-SAHA conjugated藥物，在DSS誘發結腸炎之動物模式具有預防與治療之作用，可減緩DSS造成之體重減輕及臨床症狀表徵如腹瀉及糞便潛血，亦可恢復變短結腸之長度，以及抑制Th1型細胞激素之釋放。JMF-1可保護腸道內皮不受破壞，維持crypts完整或重建發炎之黏膜結構，且發炎細胞之浸潤較輕微。此外，我們發現HCT116人類大腸直腸癌細胞具癌幹細胞族群，會形成tumorspheres、有較多ALDH+族群及具高度致瘤之能力，JMF-1可抑制colonospheres形成及癌幹細胞之生長，也可抑制colonosphere-induced xenograft之腫瘤生長並縮小體積，因此JMF-1可預防並治療結腸炎，也能降低癌幹細胞族群，是具潛力之抗發炎和抗癌藥物。

關鍵字

HDAC 抑制劑 ； 結腸炎 ； 癌幹細胞

並列摘要

Inflammatory bowel disease (IBD) is a lifelong manifestation. Currently, there is no medication to cure it, and just to keep symptoms under control. IBD patients are at increased risk for the development of colorectal cancer, one of the reasons is that cancer stem cells (CSCs) are out of control. The aim of the present study was to elucidate the beneficial effect of JMF-1, a statin-SAHA conjugated compound, on colonic mucosal damage and on the inflammatory response in dextran sulfate sodium (DSS)-induced colitis model. In acute inflammation murine model, JMF-1 showed both preventive and therapeutic effect. It attenuated DSS-induced weight loss, diarrhea, hematochezia and shortening of colon length, and also inhibited Th1 type cytokine release. JMF-1-treated mice completely maintained crypts architecture or only showed mild crypts disruption and a scanty infiltration of inflammatory cells. We also found that human colorectal cancer HCT116 cells had a small population of CSCs, characterized by tumorspheres formation and high ALDH activity and tumorigenicity. JMF-1 not only blocked self-renewal of colonospheres but also decreased CSCs population. Furthermore, JMF-1 repressed colonosphere-induced xenograft expansion. Taken together, JMF-1 might be a potential agent for acute colitis, and also a promising agent for targeting CSCs to prevent colorectal cancer development.

並列關鍵字

HDAC inhibitor ； colitis ； cancer stem cells

參考文獻

Abrahamsson, A. E., I. Geron, et al. (2009). "Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation." Proc Natl Acad Sci U S A 106(10): 3925-3929.

Agarwal, B., S. Bhendwal, et al. (1999). "Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells." Clin Cancer Res 5(8): 2223-2229.

Al-Hajj, M., M. S. Wicha, et al. (2003). "Prospective identification of tumorigenic breast cancer cells." Proc Natl Acad Sci U S A 100(7): 3983-3988.

Anton Aparicio, L. M., R. Garcia Campelo, et al. (2007). "Prostate cancer and Hedgehog signalling pathway." Clin Transl Oncol 9(7): 420-428.

Axelsson, L. G., E. Landstrom, et al. (1998). "Experimental colitis induced by dextran sulphate sodium in mice: beneficial effects of sulphasalazine and olsalazine." Aliment Pharmacol Ther 12(9): 925-934.