氨基二硫代甲酸酯类化合物IC5抑制结直肠癌细胞增殖及干预炎症性肠病相关结直肠癌发展

doi:10.5246/jcps.2014.09.078

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (9): 610-616.DOI: 10.5246/jcps.2014.09.078

氨基二硫代甲酸酯类化合物IC5抑制结直肠癌细胞增殖及干预炎症性肠病相关结直肠癌发展

马婉婉, 唐叔南, 曹明楠, 葛泽梅, 李润涛, 余四旺^*

北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2014-05-19 修回日期:2014-06-05 出版日期:2014-09-23 发布日期:2014-06-09
通讯作者: Tel.: 861082801539
基金资助:
National Natural Science Foundation (Grant No. 81272468 and 21001011) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education.

IC5, a dithiocarbamate derivative, inhibits colon cancer cell proliferation in vitro and colitis-associated colorectal carcinogenesis in vivo

Wanwan Ma, Shunan Tang, Mingnan Cao, Zemei Ge, Runtao Li, Siwang Yu^*

Department of Chemical Biology, School of Pharmaceutical Sciences Peking University Health Science Center, Beijing 100191, China

Received:2014-05-19 Revised:2014-06-05 Online:2014-09-23 Published:2014-06-09
Contact: Tel.: 861082801539
Supported by:
National Natural Science Foundation (Grant No. 81272468 and 21001011) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education.

摘要/Abstract

摘要：

结直肠癌是发病率和死亡率较高的癌症之一, 炎症性肠病和异常的细胞增殖在结直肠癌发展过程中发挥重要作用, 所以, 抗炎和抑制细胞增殖已成为结直肠癌化学预防的主要策略。本文发现氨基二硫代甲酸酯类化合物IC5可剂量依赖性抑制人结直肠癌细胞LoVo增殖, IC₅₀约为22 μM; 同时, IC5显著诱导细胞G2/M期周期阻滞。进一步研究发现, 在LoVo细胞中, IC5可以显著抑制NF-κB信号, 因此推测IC5可能抑制炎症响应。利用氧化偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)诱导小鼠结直肠癌模型研究发现, IC5可显著抑制结直肠癌发展。AOM/DSS小鼠模型结直肠癌发生率为58.3%, 口服给予IC5 50 mg/kg和100 mg/kg可显著降低小鼠结肠癌发生率, 分别降至37.5%和25.0%。此外, IC5可降低血浆中丙氨酸转氨酶(ALT)及天冬氨酸转氨酶(AST)的水平。综上所述, IC5可干预炎症相关结直肠癌的发生发展, 作为癌症预防试剂值得继续研究。

关键词: 氨基二硫代甲酸酯类化合物, 结直肠癌, 炎症性肠病相关结直肠癌, 化学预防, 增殖, NF-κB

Abstract:

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signalingand cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC₅₀ of 22μM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-κB signaling in LoVo cells, suggesting that IC5 could inhibitinflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.

Key words: Dithiocarbamate, Colorectal cancer, Colitis-associated colorectal carcinogenesis, Chemoprevention, Proliferation, NF-κB

中图分类号:

R915

Supporting:

马婉婉, 唐叔南, 曹明楠, 葛泽梅, 李润涛, 余四旺. 氨基二硫代甲酸酯类化合物IC5抑制结直肠癌细胞增殖及干预炎症性肠病相关结直肠癌发展[J]. 中国药学(英文版), 2014, 23(9): 610-616.

Wanwan Ma, Shunan Tang, Mingnan Cao, Zemei Ge, Runtao Li, Siwang Yu . IC5, a dithiocarbamate derivative, inhibits colon cancer cell proliferation in vitro and colitis-associated colorectal carcinogenesis in vivo[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(9): 610-616.

参考文献

[1] Siegel, R.; Desantis, C.; Jemal, A. CA Cancer J. Clin. 2014, 64, 104-117.

[2] Arends, M.J. Appl. Immunohistochem. Mol. Morphol. 2013, 21, 97-102.

[3] Franks, I. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 475.

[4] Coussens, L.M.; Werb, Z. Nature. 2002, 420, 860-867.

[5] Colotta, F.; Allavena, P.; Sica, A.; Garlanda, C.; Mantovani, A. Carcinogenesis. 2009, 30, 1073-1081.

[6] Grivennikov, S.I.; Greten, F.R.; Karin, M. Cell. 2010, 140, 883-899.

[7] Feagins, L.A.; Souza, R.F.; Spechler, S.J. Nat. Rev. Gastroenterol. Hepatol. 2009, 6, 297-305.

[8] Stormont, J.M.; Shah, A.N.; Sharma, A.K.; Saubermann, L.J.; Farmer, R.G. Am. J. Gastroenterol. 2013, 108, 1535.

[9] Ryan, B.M.; Russel, M.G.; Langholz, E.; Stockbrugger, R.W. Am. J. Gastroenterol. 2003, 98, 1682-1687.

[10] Fernandez Calderon, M.; Betes Ibanez, M.T. An Sist Sanit Navar. 2012, 35, 261-267.

[11] Karin, M.; Greten, F.R. Nat. Rev. Immunol. 2005, 5, 749-759.

[12] Atreya, I.; Atreya, R.; Neurath, M.F. J. Intern. Med. 2008, 263, 591-596.

[13] Wong, E.T.; Tergaonkar, V. Clin. Sci. (Lond). 2009, 116, 451-465.

[14] Kojima, M.; Morisaki, T.; Sasaki, N.; Nakano, K.; Mibu, R. Tanaka, M.; Katano, M. Anticancer Res. 2004, 24, 675-681.

[15] Rogler, G.; Brand, K.; Vogl, D.; Page, S.; Hofmeister, R.; Andus, T.; Knuechel, R.; Baeuerle, P.A.; Scholmerich, J.; Gross, V. Gastroenterology. 1998, 115, 357-369.

[16] Greten, F.R.; Eckmann, L.; Greten, T.F. Park, J.M.; Li, Z.W.; Egan, L.J.; Kagnoff, M.F.; Karin, M. Cell. 2004, 118, 285-296.

[17] Hanahan, D.; Weinberg, R.A. Cell. 2011, 144, 646-674.

[18] Schreck, R.; Meier, B.; Mannel, D.N.; Droge, W.; Baeuerle, P.A. J. Exp. Med. 1992, 175, 1181-1194.

[19] Bach, S.P.; Chinery, R.; O'Dwyer, S.T.; Potten, C.S.; Coffey, R.J.; Watson, A.J. Gastroenterology. 2000, 118, 81-89.

[20] Liu, S.F.; Ye, X.; Malik, A.B. Circulation. 1999, 100, 1330-1337.

[21] Zhang, N.; Guo, W.; Wang, L.; Huang, W.; Xu, B.; Ge, Z.; Li, M.; Li, R.T.; Cui, J.R. Anticancer Drugs. 2008, 19, 593-598.

[22] Li, Y.B.; Wang, Z.Q.; Yan, X.; Chen, M.W.; Bao, J.L.; Wu, G.S.; Ge, Z.M.; Zhou, D.M.; Wang, Y.T.; Li, R.T. Cancer Lett. 2013, 340, 88-96.

[23] Neufert, C.; Becker, C.; Neurath, M.F. Nat. Protoc. 2007, 2, 1998-2004.

[24] Tanaka, T.; Kohno, H.; Suzuki, R.; Yamada, Y.; Sugie, S.; Mori, H. Cancer Sci. 2003, 94, 965-973.

[25] Hogarth, G. Mini Rev. Med. Chem. 2012, 12, 1202-1215.

[26] Cvek, B. Mini Rev. Med. Chem. 2012, 12, 1173.

[27] Yang, S.Y.; Sales, K.M.; Fuller, B.; Seifalian, A.M.; Winslet, M.C. Trends Mol. Med. 2009, 15, 225-233.

[28] Hagar, H.H.; El-Medany, A.; El-Eter, E.; Arafa, M. Eur. J. Pharmacol. 2007, 554, 69-77.

[29] Viatour, P.; Merville, M.P.; Bours, V.; Chariot, A. Trends Biochem. Sci. 2005, 30, 43-52.

[30] Young, M.; Ordonez, L.; Clarke, A.R. Mol. Oncol. 2013, 7, 178-189.

[31] De Robertis, M.; Massi, E.; Poeta, M.L.; Carotti, S.; Morini, S.; Cecchetelli, L.; Signori, E.; Fazio, V.M. J. Carcinog. 2011, 10, 9.

[32] Perse, M.; Cerar, A. J. Biomed. Biotechnol. 2012, 2012, 718617.

[33] Subramanian, V.; Logan, R.F. Best Prac. Res. Clin. Gastroenterology. 2011, 25, 593-606.

[34] Foral, P.A.; Nystrom, K.K.; Wilson, A.F.; Christensen, C.M. Drugs Today. 2003, 39, 939-948.

[35] Tanaka, T.; Yasui, Y.; Tanaka, M.; Tanaka, T.; Oyama, T.; Rahman, K.M. Chem. Biol. Interact. 2009, 177, 128-136.

氨基二硫代甲酸酯类化合物IC5抑制结直肠癌细胞增殖及干预炎症性肠病相关结直肠癌发展

IC5, a dithiocarbamate derivative, inhibits colon cancer cell proliferation in vitro and colitis-associated colorectal carcinogenesis in vivo

RichHTML

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	赵炎葱, 王丽, 曾静静, 李景华. 新穿心莲内酯/β-环糊精包合物的分子结构及抗增殖作用研究[J]. 中国药学(英文版), 2023, 32(6): 427-434.
[2]	赵炎葱, 龚慧媛, 李景华. 过表达的人β防御素-3可抑制结肠癌细胞增殖、迁移和细胞周期[J]. 中国药学(英文版), 2023, 32(4): 250-259.
[3]	丁宁, 张涛, 罗吉, 刘皓辰, 邓宇, 何永恒. 基于网络药理学和分子对接探究白芍七物汤治疗结直肠癌的作用机制[J]. 中国药学(英文版), 2023, 32(1): 17-31.
[4]	洪倩, 王增慧, 杨阳, 高璐, 闫兆. 银杏二萜内酯葡胺注射液通过调控炎症和凋亡信号通路减轻OGD/R诱导的细胞损伤[J]. 中国药学(英文版), 2020, 29(7): 455-469.
[5]	蒋雯, 孙超, 王珏, 辛倩, 李开霖, 亓同钢, 栾云. 黄芩苷通过抑制血管重构对实验性肺动脉高压的治疗作用研究[J]. 中国药学(英文版), 2020, 29(10): 719-728.
[6]	权栩, 顾彩虹, 严峰, 高垚垚, 陈琳, 卫榕, 颜丙春, 胡荣. 猪胎盘肽通过提高TrkB和BDNF水平及促进神经母细胞增殖和分化延缓D-半乳糖诱导的小鼠衰老[J]. 中国药学(英文版), 2019, 28(10): 739-748.
[7]	应茵, 孙云峰, 李宏春, 羊波, 王晖, 吴青梅, 黄萍. 艾叶油对肺动脉高压大鼠的干预研究[J]. 中国药学(英文版), 2018, 27(3): 183-192.
[8]	张烨, 郑丹萍, 水梦洋, 刘晔, 刘晓岩, 王银叶. 新化合物W026B通过抑制炎性细胞因子的产生减轻缺血性脑损伤, 与tPA合用作用增强[J]. 中国药学(英文版), 2018, 27(10): 675-685.
[9]	杨思敏, 余四旺. 北京大学药学院举办癌症化学预防论坛[J]. 中国药学(英文版), 2016, 25(9): 704-706.
[10]	李方园, 张贵育, 欧日兰, 王莹, 戚笑笑, 刘中秋, 卢琳琳. 中草药对幽门螺旋杆菌导致的胃癌的预防作用[J]. 中国药学(英文版), 2016, 25(4): 250-265.
[11]	陈溢欣, 袁霞, 葛泽梅, 冉福香, 吴军, 李润涛, 崔景荣. 新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究[J]. 中国药学(英文版), 2014, 23(9): 601-609.
[12]	潘鑫, 李金霞, 董发勤, 邓建军, 袁兰, 王夔, 余四旺^*. 氯化镧通过细胞周期机制促进NIH 3T3小鼠胚胎成纤维细胞增殖[J]. , 2013, 22(1): 64-70.
[13]	蒋晓, 袁霞, 楚明明, 郭维, 刘敬弢, 冉褔香, 葛泽梅, 李润涛^, 崔景荣^. 化合物209对人结直肠癌细胞HT-29的体内和体外作用[J]. , 2013, 22(1): 89-94.
[14]	贾琳, 徐波, 郭维, 葛泽梅, 李润涛, 崔景荣^*. TM208与5-氟尿嘧啶联合应用对小鼠肝癌H22移植瘤的抗肿瘤作用及其机制研究[J]. , 2011, 20(6): 615-626.
[15]	陈新, 修贺明, 姜慧卿^*. 苏拉明在肝纤维化大鼠肝星状细胞增殖和凋亡中的作用[J]. , 2011, 20(4): 415-420.