Inhibitory Effects of Low-Dose Aloe-Emodin on the Development of Colorectal Tumors in Min Mice

  • Shimpo, Kan (Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University) ;
  • Chihara, Takeshi (Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University) ;
  • Kaneko, Takaaki (Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University) ;
  • Beppu, Hidehiko (Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University) ;
  • Wakamatsu, Kazumasa (Department of Chemistry, Fujita Health University School of Health Sciences) ;
  • Shinzato, Masanori (Department of Pathology, Fujita Health University School of Health Sciences) ;
  • Yukitake, Jun (Department of Clinical Immunology, Fujita Health University School of Health Sciences) ;
  • Sonoda, Shigeru (Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University)
  • Published : 2014.07.30


Aloe-emodin (AE), a natural anthraquinone compound, has been reported to exhibit anticancer activity in various cancer cell lines and anti-inflammatory effects in murine macrophages. In the present study, we investigated the cancer chemopreventive effects of AE in an Apc-deficient Min mouse model. In the first experiment, male Min mice were fed a basal diet or diets containing 5 ppm AE and 10 ppm AE for 12 weeks. The dietary administration of 5 ppm AE significantly reduced the number of colorectal tumors. In a second experiment, we investigated the effects of AE on colitis-related colon carcinogenesis in Min mouse treated with dextran sodium sulfate (DSS). Female Min mice were administered 1% DSS in their drinking water for 7 days. AE was given to mice in their diet at a dose of 5 or 50 ppm for 5 weeks. Feeding with AE significantly reduced the number of colorectal tumors. When proliferation of cells in normal-appearing colonic mucosa was assessed by monoclonal anti-rat Ki-67 antibody (MIB-5) immunohistochemistry in experiments 1 and 2, the AE treatment significantly decreased the mean MIB-5-labeling index. These results suggest that the dietary administration of low-dose AE may have chemopreventive effects against development of colorectal tumors in Min mice, possibly in part by reducing cell proliferation in colorectal mucosa.


Supported by : Japan Society for the Promotion of Science (JSPS) KAKENHI


  1. Arosio B, Gagliano N, Fusaro LMP, et al (2000). Aloe-emodin quinone pretreatment reduces acute liver injury induced by carbon tetrachloride. Pharmacol Toxicol, 87, 229-33.
  2. Boudreau MD, Beland FA, Nichols JA, Pogribna M (2013a). Toxicology and carcinogenesis studies of a noncolorized whole leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats and B6C3F1 mice (drinking water study). Natl Toxicol Program Tech Rep Ser, 577, 1-266.
  3. Boudreau MD, Mellick PW, Olson GR, et al (2013b). Clear evidence of carcinogenic activity by a whole-leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats. Toxicol Sci, 131, 26-39.
  4. Budda S, Butryee C, Tuntipopipat S, et al (2011). Suppressive effects of Moringa oleifera Lam pod against mouse colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. Asian Pac J Cancer Prev, 12, 3221-8.
  5. Chen R, Zhang J, Hu Y, et al (2014). Potential antineoplastic effects of aloe-emodin: a comprehensive review. Am J Chin Med, 42, 275-88.
  6. Chihara T, Shimpo K, Beppu H, et al (2005). Effect of aloeemodin on proliferation of various human cancer cell lines. Fujita-Gakuen Igakkaishi, 29, 73-6.
  7. Chihara T, Shimpo K, Kaneko T, et al (2009). Inhibitory effects of high temperature- and pressure-treated garlic on formation of 1,2-dimethylhydrazine-induced mucin-depleted foci and $O_{6}$-methylguanine DNA adducts in the rat colorectum. Asian Pac J Cancer Prev, 10, 827-31.
  8. Chihara T, Shimpo K, Kaneko T, et al (2010). Inhibition of 1,2-dimethylhydrazine-induced mucin-depleted foci and O6-methylguanine DNA adducts in the rat colorectum by boiled garlic powder. Asian Pac J Cancer Prev, 11, 1301-4.
  9. Chihara T, Shimpo K, Beppu H, et al (2013). Reduction of intestinal polyp formation in Min mice fed a high-fat diet with Aloe vera gel extract. Asian Pac J Cancer Prev, 14, 4435-40.
  10. Elsohly MA, Gul W, Avula B, Khan IA (2007). Determination of the anthraquinones aloe-emodin and aloin-A by liquid chromatography with mass spectrometric and diode array detection. J AOAC Int, 90, 28-42.
  11. Hamiza OO, Rehman MU, Khan R, et al (2014). Chemopreventive effects of aloin against 1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats. Hum Exp Toxicol, 33, 148-63.
  12. Harlev E, Nevo E, Lansky EP, Ofir R, Bishayee A (2012). Anticancer potential of aloes: antioxidant, antiproliferative, and immunostimulatory attributes. Planta Med, 78, 843-52.
  13. He L, Bi JJ, Guo Q, Yu Y, Ye XF (2012). Effects of emodin extracted from Chinese herbs on proliferation of non-small cell lung cancer and underlying mechanisms. Asian Pac J Cancer Prev, 13, 1505-10.
  14. Huang Q, Lu G, Shen HM, Chung MC, Ong CN (2007). Anticancer properties of anthraquinones from rhubarb. Med Res Rev, 27, 609-30.
  15. Huang PH, Huang CY, Chen MC, et al (2013). Emodin and aloe-emodin suppress breast cancer cell proliferation through ER $\alpha$ inhibition. Evid Based Complement Alternat Med, 2013, 376123.
  16. Jacoby RF, Marshall DJ, Newton MA, et al (1996). Chemoprevention of spontaneous intestinal adenomas in the $Apc^{Min}$ mouse model by the nonsteroidal anti-inflammatory drug piroxicam. Cancer Res, 56, 710-4.
  17. Kang JS, Kim TM, Shim TJ, et al (2012). Modifying effect of diallyl sulfide on colon carcinogenesis in C57BL/6J-$Apc^{Min/+}$ mice. Asian Pac J Cancer Prev, 13, 1115-8.
  18. Katsuki T, Hirata K, Ishikawa H, et al (2006). Aged garlic extract has chemopreventative effects on 1,2-dimethylhydrazineinduced colon tumors in rats. J Nutr, 136, 847-51.
  19. Kohno H, Takahashi M, Yasui Y, et al (2007). A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male $Apc^{Min/+}$ mice. Int J Cancer, 121, 506-13.
  20. Komatsu K, Nagayama Y, Tanaka K, et al (2006). Development of a high performance liquid chromatographic method for systematic quantitative analysis of chemical constituents in rhubarb. Chem Pharm Bull, 54, 941-7.
  21. Matsuda Y, Yokohira M, Suzuki S, et al (2008). One-year chronic toxicity study of Aloe arborescens Miller var. natalensis Berger in Wistar Hannover rats. A pilot study. Food Chem Toxicol, 46, 733-9.
  22. McCart AE, Vickaryous NK, Silver A (2008). Apc mice: models, modifiers and mutants. Pathol Res Pract, 204, 479-90.
  23. Mori H, Sugie S, Niwa K, Takahashi M, Kawai K (1985). Induction of intestinal tumours in rats by chrysazin. Br J Cancer, 52, 781-3.
  24. Mori H, Sugie S, Niwa K, et al (1986). Carcinogenicity of chrysazin in large intestine and liver of mice. Jpn J Cancer Res, 77, 871-6.
  25. Mori H, Sugie S, Yoshimi N, Hara A, Tanaka T (1999). Control of cell proliferation in cancer prevention. Mutat Res, 428, 291-8.
  26. Muskhelishvili L, Latendresse JR, Kodell RL, Henderson EB (2003). Evaluation of cell proliferation in rat tissues with BrdU, PCNA, Ki-67 (MIB-5) immunohistochemistry and in situ hybridization for histone mRNA. J Histochem Cytochem, 51, 1681-8.
  27. Nesslany F, Simar-Meintieres S, Ficheux H, Marzin D (2009). Aloe-emodin-induced DNA fragmentation in the mouse in vivo comet assay. Mutat Res, 678, 13-9.
  28. Ngo SN, Williams DB, Cobiac L, Head RJ (2007). Does garlic reduce risk of colorectal cancer? A systematic review. J Nutr, 137, 2264-9.
  29. Niho N, Takahashi M, Kitamura T, et al (2003). Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res, 63, 6090-5.
  30. Pandiri AR, Sills RC, Hoenerhoff MJ, et al (2011). Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors. Toxicol Pathol, 39, 1065-74.
  31. Pandurangan AK, Esa NM (2013). Dietary non-nutritive factors in targeting of regulatory molecules in colorectal cancer: an update. Asian Pac J Cancer Prev, 14, 5543-52.
  32. Park MY, Kwon HJ, Sung MK (2009). Evaluation of aloin and aloe-emodin as anti-inflammatory agents in aloe by using murine macrophages. Biosci Biotechnol Biochem, 73, 828-32.
  33. Park MY, Kwon HJ, Sung MK (2011). Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model. Life Sci, 88, 486-92.
  34. Pecere T, Gazzola MV, Mucignat C, et al (2000). Aloe-emodin is a new type of anticancer agent with selective activity against neuroectodermal tumors. Cancer Res, 60, 2800-4.
  35. Shimpo K, Chihara T, Beppu H, et al (2001). Inhibition of azoxymethane-induced aberrant crypt foci formation in rat colorectum by whole leaf Aloe arborescens Miller var. natalensis Berger. Phytother Res, 15, 705-11.
  36. Shimpo K, Chihara T, Shinzato M, et al (2003). Reduction of 1,2-dimethylhydrazine-induced colorectal proliferative lesions in mice by Aloe arborescens var. natalensis (Kidachi aloe). Pharm Biol, 41, 631-6.
  37. Shimpo K, Beppu H, Chihara T, et al (2006). Effects of Aloe arborescens ingestion on azoxymethane-induced intestinal carcinogenesis and hematological and biochemical parameters of male F344 rats. Asian Pac J Cancer Prev, 7, 585-90 (in Japanese).
  38. Shimpo K, Kaneko T, Chihara T, et al (2009). Effect of dietary administration of aloe-emodin for 5 weeks on cell proliferation of colonic mucosa in mice: a preliminary report. Med Biol, 153, 218-24.
  39. Siegers CP (1992). Anthranoid laxatives and colorectal cancer. Trends Pharmacol Sci, 13, 229-31.
  40. Siegers CP, von Hertzberg-Lottin E, Otte M, Schneider B (1993). Anthranoid laxative abuse - a risk for colorectal cancer? Gut, 34, 1099-101.
  41. Suboj P, Babykutty S, Srinivas P, Gopala S (2012a). Aloe emodin induces G2/M cell cycle arrest and apoptosis via activation of caspase-6 in human colon cancer cells. Pharmacology, 89, 91-8.
  42. Suboj P, Babykutty S, Valiyaparambil Gopi DR, et al (2012b). Aloe emodin inhibits colon cancer cell migration/ angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of $NF-{\kappa}B$. Eur J Pharm Sci, 45, 581-91.
  43. Tanaka T, Kohno H, Suzuki R, et al (2006). Dextran sodium sulfate strongly promotes colorectal carcinogenesis in $Apc^{Min/+}$ mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer, 118, 25-34.
  44. van Gorkom BAP, De Vries EGE, Karrenbeld A, Kleibeuker JH (1999). Anthranoid laxatives and their potential carcinogenic effects. Aliment Pharmacol Ther, 13, 443-52.
  45. Watanabe K, Kawamori T, Nakatsugi S, Wakabayashi K (2000). COX-2 and iNOS, good targets for chemoprevention of colon cancer. Biofactors, 12, 129-33.
  46. Yamada Y, Mori H (2007). Multistep carcinogenesis of the colon in $Apc^{Min/+}$ mouse. Cancer Sci, 98, 6-10.
  47. Yokohira M, Matsuda Y, Suzuki S, et al (2009). Equivocal colonic carcinogenicity of Aloe arborescens Miller var. natalensis Berger at high-dose level in a Wistar Hannover rat 2-y study. J Food Sci, 74, 24-30.
  48. Xu L, Chan CO, Lau CC, et al (2012). Simultaneous determination of eight anthraquinones in Semen Cassiae by HPLC-DAD. Phytochem Anal, 23, 110-6.

Cited by

  1. L. extract on oral cancer cells vol.32, pp.10, 2017,