Chemopreventive Effects of Elm Tree Root Extract on Colonic Aberrant Crypt Foci Induced by 1,2-Dimethylhydrazine in F344 Rats

  • Kwon, Hyun-Jung (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Kim, Tae-Myoung (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Ryu, Jae-Myun (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Son, Seung-Hwan (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Hong, Jin-Tae (College of Pharmacy, Chungbuk National University) ;
  • Jeong, Heon-Sang (College of Agriculture, Life & Environment Sciences, Chungbuk National University) ;
  • Kang, Jin-Seok (Department of Biomedical Laboratory Science, Namseoul University) ;
  • Ahn, Ji-Yun (Korea Food Research Institute) ;
  • Kim, Sung-Ran (Korea Food Research Institute) ;
  • Ha, Tae-Youl (Korea Food Research Institute) ;
  • Kim, Dae-Joong (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University)
  • Published : 2008.09.30


Cancer-preventive effects of ethanol extract of elm tree root (EEE) were investigated. In the in vitro cytotoxicity assay, colon cancer cells were incubated with a chloroform fraction of EEE (CF-EEE). CF-EEE significantly inhibited the proliferation of cells and induced apoptotic cell death in a dose-dependent manner. For the assessment of chemopreventive efficacy in vivo, male F344 rats were fed with EEE (0.5 or 1%) in diet for 8 weeks, and were subcutaneously injected with 1,2-dimethylhydrazine (DMH) to induce colonic aberrant crypt foci (ACF). EEE (0.5 and 1%) significantly decreased both the numbers of AC (1191.1/colon) and ACF (529.3/colon) induced by DMH. In addition, in the Western blot analysis on the colonic mucosa, administration of EEE triggered expression of caspase-3, a key factor of an apoptotic cascade. These results suggest that extract of elm tree root may have potential chemopreventive principles that lead to apoptosis of cancer cells, and thereby suppress colorectal carcinogenesis during the initiation stage.


elm tree root;colon cancer;aberrant crypt foci (ACF);apoptosis;caspase-3


  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. 2005. Cancer statistics. CA Cancer J Clin 55: 10-30
  2. Vital Statistics Division. 2004. Annual Report on the Cause of Death Statistics, Korea National Statistical Office, Seoul
  3. Reddy BS. 2000. The Fourth DeWitt S. Goodman lecture. Novel approaches to the prevention of colon cancer by nutritional manipulation and chemoprevention. Cancer Epidemiol Biomarkers Prev 9: 239-247
  4. Newmark HL, Lipkim M, Kopelovich L, Liu Y, Fan K, Shinozaki H. 2001. A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis 22: 1871-1875
  5. Gupta RA, Dubois RN. 2001. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1: 11-21
  6. Johnson IT. 2002. Anticarcinogenic effects of diet-related apoptosis in the colorectal mucosa. Food Chem Toxicol 40: 1171-1178
  7. Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell 61: 759-767
  8. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakumura Y, White R, Smits AMM, Bos JL. 1988. Genetic alterations during colorectal tumor development. N Engl J Med 319: 525-532
  9. Ward JM. 1974. Morphogenesis of chemically induced neoplasm of the colon and small intestine in rats. Lab Invest 30: 505-513
  10. Brady JF, Li D, Ishizaki H, Yang CS. 1988. Effect of diallyl sulfide on rat liver microsomal nitrosamine metabolism and other monooxygenase activities. Cancer Res 48: 5937-5940
  11. Bird RP. 1987. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 37: 147-151
  12. Bird RP. 1995. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett 93: 55-71
  13. Bird RP. 1991. Effect of cholic acid on the number and growth of aberrant crypt foci: putative preneoplastic lesions. Proc Am Assoc Cancer Res 32: 76-81
  14. Archer MC, Bruce WR, Chan CC, Corpet DF, Medline A, Roncucci I, Stamp D, Zhand XM. 1992. Aberrant crypt foci and microadenoma as marker for colon cancer. Envion Health Perspect 98: 195-197
  15. Bird RP, McLellan EA, Bruce WR. 1989. Aberrant crypts, putative precancerous lesions, in the study of the role of diet in the aetiology of colon cancer. Cancer Surv 8: 189-200
  16. Bird RP, Pretlow TP. 1992. Letter to the Editor. Cancer Res 52: 4291-4292
  17. Pereira MA, Barnes LH, Rassman VL, Kelloff GV, Steele VE. 1994. Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents. Carcinogenesis 15: 1049-1054
  18. Wattenberg LW. 1997. An overview of chemoprevention: current status and future prospects. Proc Soc Exp Biol Med 216: 133-141
  19. Tanaka T, Kohno H, Mori H. 2001. Chemoprevention of colon carcinogenesis by dietary non-nutrientive compounds. Asian Pac J Cancer Prev 2: 165-177
  20. Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Malon WA, Boone CW, Kopelovich L, Hawk ET, Liberman R, Lawrence JA, Ali I, Viner JL, Sigman CC. 2000. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr 130: 467-471
  21. Lim KT, Chun H, Kitts DD. 2001. Anti-oxidant activity of a Rhus verniciflua Stokes ethanol extract. Food Chem Toxicol 39: 229-237
  22. Lee JC, Lim KT. 2001. Inhibitory effects of the ethanol extract of Ulmus Davidiana on apoptosis induced by glucose-glucose oxidase and cytokine production in cultured mouse primary immune cells. J Biochem Mol Biol 34: 463-471
  23. Kim HK, Lim YM, Kim DK, Nho YC. 2008. Effect of natural extracts mixture from Houttuynia cerdata and Ulmus davidiana var. japonica in mast cell-induced allergic inflammatory response. Lab Anim Res 24: 1-7
  24. Sengupta A, Shosh S, Das S. 2004. Modulatory influence of garlic and tomato on cyclooxygenase-2 activity, cell proliferation and apoptosis during azoxymethane induced colon carcinogenesis in rat. Cancer Lett 208: 127-136
  25. Volate SR, Davenport DM, Muga SJ, Wargovich MJ. 2005. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis 26: 1450-1456
  26. Kim SH, Hwang KT, Park JC. 1992. Isolation of flavonoids and determination of rutin from the leaves of Ulmus parviflora. Kor J Pharmacogn 23: 229-233
  27. Lee SJ, Heo KS, OH PS, Lim K, Lim KT. 2004. Glycoprotein isolated from Ulmus davidiana Nakai inhibits TPA-induced apoptosis through nuclear factor-kappa B in NIH/3T3 cells. Toxicol Lett 146: 159-174
  28. Ko JH, Lee SJ, Lim KT. 2005. 116 kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN) inhibits glucose/glucose oxidase (G/GO)-induced apoptosis in BNL CL.2 cells. J Enthnopharmacol 100: 339-346
  29. Son YO, Lee KY, Choi KC, Chung Y, Kim JG, Jeon YM, Jang YS, Lee JC. 2004. Inhibitory effects of glycoprotein-120 (G-120) from Ulmus davidiana Nakai on cell growth and activation of matrix metalloproteinases. Mol Cells 18: 163-170
  30. Choi WH, Oh YS, Ahn JW, Kim SR, Ha TY. 2005. Antioxidative and protective effects of Ulmus davidiana var. japonica extracts on glutamate-induced cytotoxicity in PC 12 Cells. Kor J Food Sci Technol 37: 479-483
  31. Pretlow TP, Barrow BJ, Ashton WS, O'Riordan MA, Pretlow TG, Jurcisek JA, Stellato TA, 1991. Aberrant crypt: putative preneoplastic foci in human colonic mucosa. Cancer Res 51: 1564-1567
  32. Pretlow TP, Roukhadze EV, O'Riordan MA, Chan JC, Amini SB, Stellato TA. 1994. Carcinoembryonic antigenin human colonic aberrant crypt foci. Gastroenterology 107: 1719-1725
  33. Roncucci L, Pedroni M, Fante R, Di Gregorio C, Ponz de Leon M. 1993. Cell kinetic evaluation of human colonic aberrant crypts. (Colorectal Cancer Study Group of the University of Modena and the Health Care District 16, Modena, Italy). Cancer Res 53: 3726-3729
  34. McLellan EA, Medline A, Bird RP. 1991. Dose response and proliferative characteristics of aberrant crypt foci: putative preneoplastic lesions in rat colon. Carcinogenesis 12: 2093-2098
  35. Siu IM, Robinson DR, Schwartz S, Kung HJ, Pretlow TG, Petersen RB, Pretlow TP. 1999. The identification of monoclonality in human aberrant crypt foci. Cancer Res 59: 63-66
  36. Fernandes AT, Litwack G, Alnemri ES. 1994. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem 269: 30761-30764
  37. Bae MA, Yamada K, Uemura D, Seu JH, Kim YH. 1998. Aburnatubolactam C, a novel apoptosis-inducing substance produced by murine Streptomyces sp. SCRC A-20. J Microbiol Biotechnol 8: 455-460
  38. Dove A. 2001. Making a living out of the art of dying. Nat Biotechnol 19: 615-619
  39. Ji L, Zhang G, Hirabayashi Y. 1995. Inhibition of tumor necrosis factor alpha- and ceramide-induced internucleosomal DNA fragmentation by herbimycin A in U937 cells. Biochem Biophys Res Commun 212: 640-647
  40. Kakeya H, Zhang HP, Kobinata K, Onose R, Onozawa C, Kudo T, Osada H. 1997. Cytotrienin A, a novel apoptosis inducer in human leukemia HL-60 cells. J Antibiot (Tokyo) 50: 370-372
  41. Yamashita N, Shin YK, Furihata K, Hayakawa Y, Seto H. 1998. New ravidomycin analogues, FE35A and FE35B, apoptosis inducers produced by Streptomyces rochei. J Antibiot (Tokyo) 51: 1105-1108
  42. Miura M, Zhu H, Rotello R, Hartweig EA, Yuan J. 1993. Induction of apoptosis in fibroblast by Il-1 beta converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75: 653-660
  43. Earnshaw WC, Martins LM, Kaufmann SH. 1999. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68: 383-424
  44. Debatin KM. 2004. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother 53: 153-159
  45. Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T. 2002. Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharmacol 50: 343-352
  46. Boatright KM, Salvesen GS. 2003. Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725-731
  47. Oltvai ZN, Milliman CL, Korsmeyer SJ. 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609-619
  48. Potten CS. 2002. Apoptosis induced in small intestinal crypts by low doses of radiation protects the epithelium from genotoxic damage. Int Congr Ser 1236: 407-413
  49. Weisburger JH. 1971. Colon carcinogens: their metabolism and mode of action. Cancer 28: 60-70<60::AID-CNCR2820280113>3.0.CO;2-U
  50. Bird RP. 1995. Further investigation of the effect of cholic acid on the induction, growth characteristics and stability of aberrant crypt foci in rat colon. Cancer Lett 88: 201-209
  51. Greenwald P, Milner JA, Anderson DE, McDonald SS. 2002. Micronutrients in cancer chemoprevention. Cancer Metastasis Rev 21: 217-230
  52. Lee SJ. 1966. Korean Folk Medicine Monographs Series No. 3. Seoul National University Press, Seoul. p 39
  53. Jun CD, Pae HO, Kim YC, Jeong SJ, Yoo JC, Lee EJ, Choi BM, Chae SW, Park RK, Chung HT. 1998. Inhibition of nitric oxide synthesis by butanol fraction of the methanol extract of Ulmus davidiana in murine macrophages. J Ethnopharmacol 62: 129-135
  54. Eun JS, Song WY. 1994. The combined effects of n-BuOH fraction of ulmi cortex and anticancer drugs on cancer cell lines. Kor J Pharmacogn 25: 144-152
  55. Moon YH, Rim GR. 1995. Studies on the constituents of Ulmus parvifolia. Kor J Pharmacogn 26: 1-7
  56. Yang YL, Kim YJ. 2001. Immunostimulating exopolysaccharide with anticancer activity from Enterobacter sp. SSY (KCTC 0687BP) screened from Ulmus parvifolia. Kor J Biotechnol Bioeng 16: 554-561
  57. Lee JC, Lee KY, Son YO, Choi KC, Kim J, Truong TT, Jang YS. 2005. Plant-originated glycoprotein, G-120, inhibits the growth of MCF-7 cells and induces their apoptosis. Food Chem Toxicol 43: 961-968
  58. Dashwood RH, Xu M, Orner GA, Horio DT. 2001. Colonic cell proliferation, apoptosis and aberrant crypt foci development in rats given 2-amino-3-methylimidaz. Eur J Cancer Prev 10: 139-145
  59. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37-43
  60. Yuan J, Murrell GA, Trickett A, Wang MX. 2003. Involvement of cytochrome c release and caspase-3 activation in the oxidative stress-induced apoptosis in human tendon fibroblasts. Biochim Biophys Acta 1641: 35-41
  61. Barnhart BC, Alappat EC, Peter ME. 2003. The CD95 type I/type II model. Semin Immunol 15: 185-193
  62. Fan TJ, Han LH, Cong RS, Lizng J. 2005. Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai) 37: 719-727

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