생명과학회지 (Journal of Life Science)

  • 제29권9호
  • /
  • Pages.941-948
  • /
  • 2019
  • /
  • 1225-9918(pISSN)
  • /
  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
권호 표지
DOI QR코드

DOI QR Code

AOM/DSS로 유도된 마우스 대장암 모델에서의 Ziyuglycoside-II의 항염증효과

Ziyuglycoside II Attenuates Tumorigenesis in Experimental Colitis-associated Colon Cancer

  • 천혜진 (대구가톨릭대학교 의생명화학부 의생명과학전공) ;
  • 김진경 (대구가톨릭대학교 의생명화학부 의생명과학전공)
  • Cheon, Hye-Jin (Department of Biomedical Science, Daegu Catholic University) ;
  • Kim, Jin-Kyung (Department of Biomedical Science, Daegu Catholic University)
  • 투고 : 2019.07.05
  • 심사 : 2019.07.31
  • 발행 : 2019.09.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Ziyuglycoside-II ($3{\beta}-3-{\alpha}$-1-arabinopyranosyloxy-19-hydroxyurs-12-en-28-oicacid)는 오이풀(Sanguisorba officinalis L.)의 주요 활성 화합물 중 하나로 지혈작용, 항산화활성, 항염증활성 등의 활성이 보고되어 있다. 그러나 염증성 대장암에서의 ziyuglycoside-II의 활성에 관해서는 아직 보고되지 않아 본 연구에서 azoxymethane (AOM)/dextran sulfate sodium (DSS)으로 유발된 대장암 모델에서 ziyuglycoside-II 항종양활성을 조사하였다. 염증성 대장암을 유발하기 위해 BALB/c 마우스에게 AOM을 1회 복강 주사하고 AOM 투여 1주일 후 총 3 cycle의 2% 농도의 DSS를 음용수로 공급 하였다. Ziyuglycoside-II (1 또는 5 mg/kg)는 1주일에 3회 경구 투여하고, 64일에 대장을 적출하였다. 대장 조직에서의 종양 개수를 관찰한 결과 ziyuglycoside-II의 투여가 종양의 형성을 유의적으로 감소시키는 것을 확인하였다. 또한 Western blot 방법과 면역 조직학 분석의 결과, ziyuglycoside-II의 투여가 대장 조직에서 nuclear factor kappa-B 양성 세포와 염증 관련 단백질의 양을 현저히 감소시킴을 관찰하였다. 또한 ziyuglycoside-II 투여에 의해 대장조직내의 세포사멸이 촉진되었고 cleaved-caspase 3, cleaved-caspase 7과 같은 세포사멸 관련 단백질의 발현이 증가함을 확인하였다. 이러한 결과는 ziyuglycoside-II의 투여가 염증반응을 억제하고 세포 자멸을 유도하여 염증성대장암의 발생을 억제함을 시사하고 있다.

Colorectal cancer is a major health problem in industrialized countries. Ziyuglycoside II ($3{\beta}-3-{\alpha}$-1- arabinopyranosyloxy-19-hydroxyurs-12-en-28-oicacid), a triterpenoid saponin isolated from the roots of Sanguisorba officinalis L., possesses antioxidant, antiangiogenic, and anticancer properties. However, the therapeutic function of ziyuglycoside II in colitis-associated colorectal carcinogenesis is undefined. In the present study, the effect of ziyuglycoside II on colitis-associated colon cancer induced in mice using azoxymethane (AOM)/dextran sulfate sodium (DSS) was explored. The AOM model recapitulates many features of human colon cancer, but it lacks an inflammatory component. DSS induces colitis and promotes AOM-induced colon cancer in mice. BALB/c mice were injected with AOM and administered 2% DSS in drinking water. The mice were given ziyuglycoside II (1 or 5 mg/kg) orally three times per week, and colonic tissue was collected at 64 days. Administration of ziyuglycoside II markedly diminished the formation of colonic tumors. Western blot and immunohistological analyses showed that ziyuglycoside II noticeably decreased nuclear factor kappa-B-positive cells and levels of inflammation-related proteins, such as inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-${\alpha}$, and interleukin-6 in colon tissue. It also prompted apoptosis. Ziyuglycoside II treatment augmented cleaved forms of caspase-3, caspase-7, and poly (ADP-ribose) polymerase in colonic tissues. In conclusion, ziyuglycoside II could defend against colitis-associated tumorigenesis in mice by inhibiting inflammation and inducing apoptosis. This shows a promising chemopreventive potential for its use in colitis-associated colon cancer.

키워드

참고문헌

  1. Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jema,l A. and Bray, F. 2017. Global patterns and trends in colorectal cancer incidence and mortality. Gut 66, 683-691. https://doi.org/10.1136/gutjnl-2015-310912
  2. Bernstein, C. N., Blanchard, J. F., Kliewer, E. and Wajda, A. 2001. Cancer risk in patients with inflammatory bowel disease: A population-based study. Cancer 91, 854-862. https://doi.org/10.1002/1097-0142(20010215)91:4<854::AID-CNCR1073>3.0.CO;2-Z
  3. Chen, J., Pitmon, E. and Wang, K. 2017. Microbiome, inflammation and colorectal cancer. Semin. Immunol. 32, 43-53. https://doi.org/10.1016/j.smim.2017.09.006
  4. Das, V., Kalita, J. and Pal, M. 2016. Predictive and prognostic biomarkers in colorectal cancer: a systematic review of recent advances and challenges. Biomed. Pharmacother. 87, 8-19.
  5. Eaden, J. A., Abrams, K. R. and Mayberry, J. F. 2001. The risk of colorectal cancer in ulcerative colitis: A meta-analysis. Gut 48, 526-535. https://doi.org/10.1136/gut.48.4.526
  6. Elmore, S. Apoptosis: A review of programmed cell death. 2007. Toxicol. Pathol. 35, 495-516. https://doi.org/10.1080/01926230701320337
  7. Francescone, R., Hou, V. and Grivennikov, S. I. 2015. Cytokines, IBD, and colitis-associated cancer. Inflamm. Bowel. Dis. 21, 409-418. https://doi.org/10.1097/MIB.0000000000000236
  8. Fujita, K., Iwama, H., Oura, K., Tadokoro, T., Samukawa, E., Sakamoto, T., Nomura, T., Tani, J., Yoneyama, H., Morishita, A., Himoto, T., Hirashima, M. and Masaki, T. 2017. Cancer therapy due to apoptosis: Galectin-9. Int. J. Mol. Sci. 18, pii: E74. https://doi.org/10.3390/ijms18010074
  9. Grivennikov, S. I. 2013. Inflammation and colorectal cancer: colitis-associated neoplasia. Semin. Immunopathol. 35, 229-244. https://doi.org/10.1007/s00281-012-0352-6
  10. Jang, E., Inn, K. S., Jang, Y. P., Lee, K. T. and Lee, J. H. 2018. Phytotherapeutic activities of Sanguisorba officinalis and its chemical constituents: A review. Am. J. Chin. Med. 46, 299-318. https://doi.org/10.1142/S0192415X18500155
  11. Keller, D. S., Windsor, A., Cohen, R. and Chand, M. 2019. Colorectal cancer in inflammatory bowel disease: review of the evidence. Tech. Coloproctol. 23, 3-13. https://doi.org/10.1007/s10151-019-1926-2
  12. Kim, H. J., Park, J. H. and Kim, J. K. 2014. Cucurbitacin-I, a natural cell-permeable triterpenoid isolated from Cucurbitaceae, exerts potent anticancer effect in colon cancer. Chem. Biol. Interact. 219, 1-8. https://doi.org/10.1016/j.cbi.2014.05.005
  13. Kim, J. K., Shin, E. K., Park, J. H., Kim, Y. H. and Park, J. H. 2010. Antitumor and antimetastatic effects of licochalcone A in mouse models. J. Mol. Med. 88, 829-838. https://doi.org/10.1007/s00109-010-0625-2
  14. Kim, Y. H., Kwon, H. S., Kim, D. H., Shin, E. K., Kang, Y. H., Park, J. H., Shin, H. K. and Kim, J. K. 2009. 3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm. Bowel. Dis. 15, 1164-1173. https://doi.org/10.1002/ibd.20917
  15. Kundu, J. K. and Surh, Y. J. 2008. Inflammation: Gearing the journey to cancer. Mutat. Res. 659, 15-30. https://doi.org/10.1016/j.mrrev.2008.03.002
  16. Liu, Y. and Zeng, G. 2012. Cancer and innate immune system interactions: Translational potentials for cancer immunotherapy. J. Immunother. 35, 299-308. https://doi.org/10.1097/CJI.0b013e3182518e83
  17. Liu, X., Cui, Y., Yu, Q. and Yu, B. 2005. Triterpenoids from Sanguisorba officinalis. Phytochemistry 66, 1671-1679. https://doi.org/10.1016/j.phytochem.2005.05.011
  18. Marusawa, H. and Jenkins, B. J. 2014. Inflammation and gastrointestinal cancer: an overview. Cancer Lett. 345, 153-156. https://doi.org/10.1016/j.canlet.2013.08.025
  19. Mitchell, J. P. and Carmody, R. J. 2018. NF-${\kappa}B$ and the Transcriptional Control of Inflammation. Int. Rev. Cell Mol. Biol. 335, 41-84. https://doi.org/10.1016/bs.ircmb.2017.07.007
  20. Nam, S. H., Lkhagvasuren, K., Seo, H. W. and Kim, J. K. 2017. Antiangiogenic effects of ziyuglycoside II, a major active compound of Sanguisorba officinalis L. Phytother. Res. 31, 1449-1456. https://doi.org/10.1002/ptr.5874
  21. Nomi, N., Kodama, S. and Suzuki, M. 2010. Toll-like receptor 3 signaling induces apoptosis in human head and neck cancer via survivin associated pathway. Oncol. Rep. 24, 225-231.
  22. Owen, H. C., Appiah, S., Hasan, N., Ghali, L., Elayat, G. and Bell, C. 2017. Phytochemical modulation of apoptosis and autophagy: strategies to overcome chemoresistance in leukemic stem cells in the bone marrow microenvironment. Int. Rev. Neurobiol. 135, 249-278. https://doi.org/10.1016/bs.irn.2017.02.012
  23. Park, J. H. and Kim, J. K. 2018. Pristimerin, a naturally occurring triterpenoid, attenuates tumorigenesis in experimental colitis-associated colon cancer. Phytomedicine 42, 164-171. https://doi.org/10.1016/j.phymed.2018.03.033
  24. Priyadarsini, R. V. and Nagini, S. 2012. Cancer chemoprevention by dietary phytochemicals: promises and pitfalls. Curr. Pharm. Biotechnol. 13, 125-136. https://doi.org/10.2174/138920112798868610
  25. Siegel, R. L., Miller, K. D., Fedewa, S. A., Ahnen, D. J., Meester, R. G. S., Barzi, A. and Jemal, A. Colorectal cancer statistics, 2017. 2017. CA. Cancer J. Clin. 67, 177-193. https://doi.org/10.3322/caac.21395
  26. Watson, A. J. An overview of apoptosis and the prevention of colorectal cancer. 2006. Crit. Rev. Oncol. Hematol. 57, 107-121. https://doi.org/10.1016/j.critrevonc.2005.06.005
  27. Zeligs, K. P., Neuman, M. K. and Annunziata, C. M. 2016. Molecular Pathways: The balance between cancer and the immune system challenges the therapeutic specificity of targeting nuclear factor-${\kappa}B$ signaling for cancer treatment. Clin. Cancer Res. 22, 4302-4308. https://doi.org/10.1158/1078-0432.CCR-15-1374
  28. Zhao, Z., He, X., Zhang, Q., Wei, X., Huang, L., Fang, J. C., Wang, X., Zhao, M., Bai, Y. and Zheng, X. 2017. Traditional uses, chemical constituents and biological activities of plants from the Genus Sanguisorba L. Am. J. Chin. Med. 45, 199-224. https://doi.org/10.1142/S0192415X17500136
  29. Zhu, A. K., Zhou, H., Xia, J. Z., Jin, H. C., Wang, K., Yan, J., Zuo, J. B., Zhu, X. and Shan, T. 2013. Ziyuglycoside II-induced apoptosis in human gastric carcinoma BGC-823 cells by regulating Bax/Bcl-2 expression and activating caspase-3 pathway. Braz. J. Med. Biol. Res. 46, 670-675. https://doi.org/10.1590/1414-431X20133050
  30. Zhu, X., Wang, K., Zhang, K., Huang, B., Zhang, J., Zhang, Y., Zhu, L., Zhou, B. and Zhou, F. 2013. Ziyuglycoside II inhibits the growth of human breast carcinoma MDA-MB- 435 cells via cell cycle arrest and induction of apoptosis through the mitochondria dependent pathway. Int. J. Mol. Sci. 14, 18041-18055. https://doi.org/10.3390/ijms140918041
  31. Zhu, X., Wang, K., Zhang, K., Zhu, L. and Zhou, F. 2014. Ziyuglycoside II induces cell cycle arrest and apoptosis through activation of ROS/JNK pathway in human breast cancer cells. Toxicol. Lett. 227, 65-73. https://doi.org/10.1016/j.toxlet.2014.03.015