Advertisement

Natural CAC chemopreventive agents from Ilex rotunda Thunb.

  • Yueqing Han
  • Lin Zhang
  • Wei Li
  • Xinran Liu
  • Jiao Xiao
  • Gang ChenEmail author
  • Ning LiEmail author
Original Paper

Abstract

Colitis-associated cancer (CAC) is one of the most serious complications of inflammatory bowel disease. The pathogenesis of CAC is complicated and so far elusive, and the anti-inflammatory effect does not assure CAC preventive activity, making it difficult to discover CAC preventive drugs. In this study, we report the CAC preventive effect of the ethyl acetate (EIR) of Ilex rotunda Thunb., a traditional Chinese herbal medicine being clinically used to treat intestinal disease. We also report the results of screening for CAC preventive agents from EIR via a nuclear factor-kappa B (NF-κB) translocation model in Caco2 cells, since activated NF-κB can be used by tumor cells at the early stage of tumorigenesis. Twenty-four components were isolated from EIR and identified by multiple chromatography and spectral analysis. MTT experiments in IEC-6 and RAW264.7 cells showed that all 24 compounds were toxic-free to normal cell lines. Furthermore, compound rotundic acid (RA) (19) exhibited an inhibitory effect on LPS-induced NF-κB translocation in Caco2 cells. Moreover, RA did not induce apoptosis in Caco2 tumor cells while possessing an anti-inflammatory effect both in immune and intestinal epithelium cells (RAW264.7 and IEC-6 cells, respectively). Removing RA (19) and its 28-O-glucopyranoside (17) from EIR definitely undermined the in vivo CAC preventive activity of EIR. Therefore, the current study suggested that RA (19) could be a potential therapeutic agent against CAC.

Keywords

Colitis-associated cancer Ilex rotunda Thunb. Inflammatory bowel disease Active ingredients Rotundic acid 

Notes

Acknowledgements

The work was supported partially by the National Natural Science Foundation of China (Grant nos. 81673323, 81872768, 81628012); the Open Research Funding of Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use (2018KF05); and the young and middle-aged teachers’ career development support plan of Shenyang Pharmaceutical University (ZCQ201701).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no disclosures to report.

Supplementary material

11418_2019_1281_MOESM1_ESM.docx (373 kb)
Supplementary material 1 (DOCX 373 kb)

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefGoogle Scholar
  2. 2.
    Breynaert C, Vermeire S, Rutgeerts F, Van AG (2008) Dysplasia and colorectal cancer in inflammatory bowel disease: a result of inflammation or an intrinsic risk? Acta Gastroenterol Belg 71:367–372Google Scholar
  3. 3.
    Grivennikov SI (2015) Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol 35:229–244CrossRefGoogle Scholar
  4. 4.
    Lakatos PLLL (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14:3937–3947CrossRefGoogle Scholar
  5. 5.
    Baumgart DC, Sandborn WJ (2012) Crohn’s disease. Lancet 380:1590–1605CrossRefGoogle Scholar
  6. 6.
    Danese S, Fiocchi C (2011) Medical progress. N Engl J Med 365:1713–1725CrossRefGoogle Scholar
  7. 7.
    Neurath MF (2014) Cytokines in inflammatory bowel disease. Nat Rev Immunol 14:329–342CrossRefGoogle Scholar
  8. 8.
    Zhu Y, Zhou J, Yi Feng, Chen LY, Zhang LH, Yang F, Zha HR, Wang XX, Han X, Shu C, Song Y, Li QJ, Guo B, Zhu B (2018) Control of intestinal inflammation, colitis-associated tumorigenesis, and macrophage polarization by fibrinogen-like protein2. Front Immunol 9:87–117CrossRefGoogle Scholar
  9. 9.
    Yang B, Zhu JP, Rong L, Jing Jin, Cao D, Hui Li, Zhou XH, Zhao ZX (2018) Triterpenoids with antiplatelet aggregation activity from Ilex rotunda. Phytochemistry 145:179–186CrossRefGoogle Scholar
  10. 10.
    Lu XH (2014) Pharmaceutical king tree. Iron Holly Guangxi Forest 1:28–29Google Scholar
  11. 11.
    Hu ZY, Tang M, Zhang QH, Zhao LC (2018) Research progress on chemical composition and pharmacological action of Ilex rotunda. J Changchun Norm Univ 37:69–74Google Scholar
  12. 12.
    Huo X, Liu D, Gao L, Li Y (2016) Flavonoids extracted from licorice prevents colitis-associated carcinogenesis in AOM/DSS mouse model. Int J Mol Sci 17:1343–1370CrossRefGoogle Scholar
  13. 13.
    Blennerhassett MG, Bovell FM, Lourenssen S, Mchugh KM (1999) Characteristics of inflammation-induced hypertrophy of rat intestinal smooth muscle cell. Dig Dis Sci 44:1265–1272CrossRefGoogle Scholar
  14. 14.
    Kyung-Sook C, Se-Yun C, Seong-Soo R, Minho L, Hyo-Jin A (2018) Chemopreventive effect of Aster glehni on inflammation-induced colorectal carcinogenesis in mice. Nutrients 10:202–213CrossRefGoogle Scholar
  15. 15.
    Rajan TS, Giacoppo S, Iori R, Rosalind G, Nicola D, Grass G, Pollastro F, Bramanti P, Mazzon E (2016) Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages. Fitoterapia 112:104–105CrossRefGoogle Scholar
  16. 16.
    Tao L, Zhang F, Hao L, Wu J, Jia J, Liu JY, Zeng LT, Zhen X (2014) 1-O-Tigloyl-1-O-deacetyl-nimbolinin B inhibits LPS-stimulated inflammatory responses by suppressing NF-κB and JNK activation in microglia cells. Pharmacol Sci 125:364–374CrossRefGoogle Scholar
  17. 17.
    Chun SC, Jee SY, Sang GL, Park SJ, Lee JR, Sang CK (2007) Anti-inflammatory activity of the methanol extract of moutan cortex in LPS-activated raw264.7 cells. Evid Based Complement Altern Med 4:327–333CrossRefGoogle Scholar
  18. 18.
    colitis-associated cancer. Cancers (Basel) 3:2811–2826CrossRefGoogle Scholar
  19. 19.
    Zhang D, Mi M, Jiang F, Sun Y, Li Y, Yang L, Fan L, Li Q, Meng J, Yue Z, Liu L, Mei Q (2015) Apple polysaccharide reduces NF-Kb mediated colitis-associated colon carcinogenesis. Nutr Cancer 67:177–190CrossRefGoogle Scholar
  20. 20.
    Li WK, Xiao PG, Chen ZL (1999) Study on chemical constituents of Huanghua Yuanzhi Chin. J Tradit Chin Med 24:477–479Google Scholar
  21. 21.
    Zhao AH, Zhao QS, Li RT, Sun HD (2004) Chemical composition of kidney tea. J Plant Diver Resour 26:563–568Google Scholar
  22. 22.
    Wang W, Yang CR, Zhang YJ (2009) Phenolic ingredients in the fruit of the fruit. Plant Diver Resour 31:284–288Google Scholar
  23. 23.
    Ming CL, Tang SA, Duan HQ (2010) Chemical consitituents from Onychium japonicum. Chin Tradit Herb Drugs 41:685–688Google Scholar
  24. 24.
    Hu J, Zhang WD, Liu RH, Zhang C, Shen YH, Xu XH, Liang MJ, Li HL (2006) Chemical constituents in root of Zanthoxylum nitidum. China J Chin Mater Med 31:1689–1691Google Scholar
  25. 25.
    Liu R, Yu SS, Pei YH (2009) Chemical constituents from leaves of Albizia chinensis. China J Chin Mater Med 34:2063–2066Google Scholar
  26. 26.
    Zhao D, Wu TY, Guan YQ, Ma GX, Zhang J, Shi LL (2017) Chemical constituents from roots of Stelleropsis tianschanica. China J Chin Mater Med 9:3379–3384Google Scholar
  27. 27.
    Wang CH, Wei PL, Yan SK, Jin HZ, Zhang DW (2014) Study on chemical constituents of ethyl acetate fraction of Minnan. Nat Prod Res Dev 26:33–37Google Scholar
  28. 28.
    Mao CM, Li SS, Xu QM, Yang SL (2016) Study on the chemical constituents of the stalk. Chin Herb Med 47:891–896Google Scholar
  29. 29.
    Meerungrueang W, Panichayupakaranant P (2014) Antimicrobial activities of some Thai traditional medical longevity formulations from plants and antibacterial compounds from Ficus foveolata. Pharm Microbiol 52:1104–1109Google Scholar
  30. 30.
    Wu Z, Ouyang M, Yang C (1999) Polyphenolic constituents of Salvia sonchifolia. Acta Bot Yunnanica 21:393–398Google Scholar
  31. 31.
    Li YS, Tian Y, Guo P, Yang JQ, Xu XD (2014) Synthesis and biological activity of caffeate derivatives. Chin Herb Med 45:3538–3542Google Scholar
  32. 32.
    Jakupovic J, Zdero C, Paredes L, Bohlmann F (1988) Sesquiterpene glycosides and other constituents from osteospermum species. Phytochemistry 27:2881–2886CrossRefGoogle Scholar
  33. 33.
    Kitagawa I, Wei H, Nagao S, Mahmud T, Kobayashi M, Uji T, Shibuya H (1996) Chem Pharm Bull 44:1162–1167CrossRefGoogle Scholar
  34. 34.
    He W, Zhang YM (2012) Study on chemical constituents of stalk. Chin Herb Med 43:1276–1279Google Scholar
  35. 35.
    Yu Y, Gao W, Yi Dai, Li XX, Li JM, Yao XS (2010) Study on lignans in gardenia. Chin Herb Med 41:509–514Google Scholar
  36. 36.
    Sun H, Zhang XQ, Cai Y, Han WL, Wang Y, Ye WC (2009) Study on chemical constituents of Ilex rotunda Thunb. Chem Ind For Prod 29:111–114Google Scholar
  37. 37.
    Nguyen HT, Ho DV, Vo HQ, Le HQ, Nquyen HM, Kodama T, Ito T, Morita H, Raal A (2017) Antibacterial activities of chemical constituents from the aerial parts of Hedyotis pilulifera. Pharm Microbiol 55:787–791Google Scholar
  38. 38.
    Xia WZ, Cui BS, Li S (2016) Study on the chemical constituents of Sijiqing. Chin Herb Med 47:1272–1277Google Scholar
  39. 39.
    Wang L, Zhang CF, Layba M, Zhang M (2011) Study on the constituents of triterpenoids and sterols from broad-leaved ebony in West Africa. Chin J Tradit Chin Med 18:2511–2514Google Scholar
  40. 40.
    Yao ZR, Li J, Zhou SX, Zhang W, Tu PF (2009) Triterpenoids in the sacral leaves. Chin J Tradit Chin Med 34:999–1001Google Scholar
  41. 41.
    Liu WJ, Peng YY, Chen H, Liu XF, Liang JY, Sun JB (2017) Triterpenoid saponins with potential cytotoxic activities from the root bark of Ilex rotunda Thunb. Chem Biodivers 2017:14Google Scholar
  42. 42.
    Li S, Zhao J, Wang W (2015) Seven new triterpenoids from the aerial parts of Ilex cornuta, and protective effects against H2O2-induced myocardial cell injury. Phytochem Lett 14:178–184CrossRefGoogle Scholar
  43. 43.
    Ratnam NM, Peterson JM, Talbert EE, Ladner KJ, Rajasekera PV, Schmidt CR, Dillhoff ME, Swanson BJ, Haverick E, Kladney RD, Williams TM, Leone GW, Wang DJ, Guttridge DC (2017) NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J Clin Invest 127:3796–3809CrossRefGoogle Scholar
  44. 44.
    Li F, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS, Sethi G (2015) NF-κB in cancer therapy. Arch Toxicol 89:711–731CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  1. 1.Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research and DevelopmentSchool of Traditional Chinese Materia Medica, Shenyang Pharmaceutical UniversityShenyangChina
  2. 2.Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan HospitalCapital Medical UniversityBeijingChina
  3. 3.Faculty of Pharmaceutical SciencesToho UniversityFunabashiJapan

Personalised recommendations