Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Feb;93(2):133–142. doi: 10.1111/j.1349-7006.2002.tb01251.x

Dietary Conjugated Linolenic Acid Inhibits Azoxymethane‐induced Colonic Aberrant Crypt Foci in Rats

Hiroyuki Kohno 1,, Rikako Suzuki 2,, Ryoko Noguchi 2,, Masashi Hosokawa 2,, Kazuo Miyashita 2,, Takuji Tanaka 1,
PMCID: PMC5926953  PMID: 11856476

Abstract

The modifying effects of dietary feeding of conjugated linolenic acid (CLN) isolated from the seeds of bitter gourd (Momordica charantia) on the development of azoxymethane (AOM)‐induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats to predict its possible cancer chemopreventive efficacy. The effect of CLN on the proliferating cell nuclear antigen (PCNA) index in colonic ACF was also examined. Rats were given subcutaneous injections of AOM (20 mg/ kg body weight) once a week for 2 weeks to induce ACF. They also received the experimental diet containing 0.01%, 0.1% or 1% CLN for 5 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (108±21/rat) at the end of the study (week 4). Dietary administration of CLN caused a significant reduction in the frequency of ACF: 87±14 (19.4% reduction, P<0.05) at a dose of 0.01%, 69±28 (36.1% reduction, P<0.01) at a dose of 0.1% and 40±d6 (63.0% reduction, P<0.001) at a dose of 1%. Also, CLN administration lowered the PCNA index and induced apoptosis in ACF. These findings might suggest possible chemopreventive activity of CLN in the early phase of colon tumorigenesis through modulation of cryptal cell proliferation activity and/or apoptosis.

Keywords: Conjugated linolenic acid, Chemoprevention, Aberrant crypt foci, PCNA index, Apoptosis

Full Text

The Full Text of this article is available as a PDF (9.9 MB).

REFERENCES

  • 1.Doll , R.The lessons of life: Keynote address to the Nutrition and Cancer Conference . Cancer Res. , 52 , 2024s – 2029s ( 1992. ). [PubMed] [Google Scholar]
  • 2.Wynder , E. L. , Kajitani , T. , Ishikawa , S. , Dodo , H. and Takano , A.Environmental factors of cancer of colon and rectum . Cancer , 23 , 1210 – 1220 ( 1969. ). [DOI] [PubMed] [Google Scholar]
  • 3.Reddy , B. S. , Tanaka , T. and Simi , B.Effect of different levels of dietary trans fat or corn oil on azoxymethane‐induced colon carcinogenesis in F344 rats . J. Natl. Cancer Inst. , 75 , 791 – 798 ( 1985. ). [PubMed] [Google Scholar]
  • 4.Bartsch , H. , Nair , J. and Owen , R. W.Dietary polyunsatu‐rated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers . Carcinogenesis , 20 , 2209 – 2218 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 5.Rao , C. V. , Hirose , Y. , Indranie , C. and Reddy , B. S.Modulation of experimental colon tumorigenesis by types and amounts of dietary fatty acids . Cancer Res. , 61 , 1927 – 1933 ( 2001. ). [PubMed] [Google Scholar]
  • 6.Fernandez , E. , Chatenoud , L. , La Vecchia , C. , Negri , E. and Franceschi , S.Fish consumption and cancer risk . Am. J. Clin. Nutr. , 70 , 85 – 90 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 7.Reddy , B. S.Dietary fat and colon cancer: animal model studies . Lipids , 27 , 807 – 813 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 8.Kohno , H. , Yamaguchi , N. , Ohdoi , C. , Nakajima , S. , Odashima , S. and Tanaka , T.Modifying effect of tuna orbital oil rich in docosahexaenoic acid and vitamin D3 on azoxymethane‐induced colonic aberrant crypt foci in rats . Oncol. Rep. , 7 , 1069 – 1074 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 9.Bird , R. P.Role of aberrant crypt foci in understanding the pathogenesis of colon cancer . Cancer Lett. , 93 , 55 – 71 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10.Hirose , M. , Masuda , A. , Ito , N. , Kamano , K. and Okuyama , H.Effects of dietary perilla oil, soybean oil and safflower oil on 7,12‐dimethylbenz[a] anthracene (DMBA) and 1,2‐dimethylhydrazine (DMH)‐induced mammary gland and colon carcinogenesis in female SD rats . Carcinogenesis , 11 , 731 – 735 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 11.Narisawa , T. , Fukaura , Y. , Yazawa , K. , Ishikawa , G. , Isoda , Y. and Nishizawa , Y.Colon cancer prevention with a small amount of dietary perilla oil high in α‐linolenic acid in an animal model . Cancer , 73 , 2069 – 2075 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 12.Onogi , N. , Okuno , M. , Komaki , H. , Kawamori , T. , Tanaka , T. , Mori , H. and Muto , Y.Suppressing effect of perilla oil on azoxymethane‐induced foci of colonic aberrant crypts in rats . Carcinogenesis , 17 , 1291 – 1296 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 13.Chin , S. F. , Liu , W. , Storkson , J. M. , Ha , Y. L. and Pariza , M. W.Dietary sources of conjugated dienoic isomers of linoleic acid, a newly recognized class of anticarcinogens . J. Food Compos. Anal , 5 , 185 – 197 ( 1992. ). [Google Scholar]
  • 14.Ip , C. , Chin , S. F. , Scimeca , J. A. and Pariza , M. W.Mammary cancer prevention by conjugated dienoic derivative of linoleic acid . Cancer Res. , 51 , 6118 – 6124 ( 1991. ). [PubMed] [Google Scholar]
  • 15.Belury , M. A. , Nickel , K. P. , Bird , C. E. and Wu , Y.Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion . Nutr. Cancer , 26 , 149 – 157 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 16.Banni , S. , Angioni , E. , Casu , V. , Melis , M. P. , Carta , G. , Corongiu , F. P. , Thompson , H. and Ip , C.Decrease in linoleic and metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid . Carcinogenesis , 20 , 1019 – 1024 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 17.Kavanaugh , C. J. , Liu , K.‐L. and Belury , M. A.Effect of dietary conjugated linoleic acid on phorbol ester‐induced PGE, production and hyperplasia in mouse epidermis . Nutr. Cancer , 33 , 132 – 138 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 18.Fritsche , J. and Steinhart , H.Analysis, occurrence, and physiological properties of trans fatty acids (TFA) with particular emphasis on conjugated linoleic acid isomers (CLA)—a review . Fett/Lipid , 100 , 190 – 210 ( 1998. ). [Google Scholar]
  • 19.Liew , C. , Schut , H. A. J. , Chin , S. F. , Pariza , M. W. and Dashwood , R. H.Protection of conjugated linoleic acids against 2‐amino‐3‐methylimidazo[4,5‐f]quinoline‐induced colon carcinogenesis in the F344 rat: a study of inhibitory mechanisms . Carcinogenesis , 16 , 3037 – 3043 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 20.Xu , M. and Dashwood , R. H.Chemoprevention studies of heterocyclic amine‐induced colon carcinogenesis . Cancer Lett. , 143 , 179 – 183 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 21.Cornelius , A. S. , Yerram , N. R. , Kratz , D. A. and Spector , A. A.Cytotoxic effect of cis‐parinaric acid in cultured malignant cells . Cancer Res. , 51 , 6025 – 6030 ( 1991. ). [PubMed] [Google Scholar]
  • 22.Igarashi , M. and Miyazawa , T.Newly recognized effect of conjugated trienoic fatty acids on cultured human tumor cells . Cancer Lett. , 148 , 173 – 179 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 23.Igarashi , M. and Miyazawa , T.Do conjugated eicosapen‐taenoic acid and conjugated docosahexaenoic acid induce apotosis via lipid peroxidation in cultured human tumor cells ? Biochem. Biophys. Res. Commun. , 270 , 649 – 656 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 24.Smith , C. R.Occurrence of unusual fatty acids in plants . Prog. Chem. Fats Other Lipids , 11 , 137 – 177 ( 1971. ). [Google Scholar]
  • 25.Badami , R. C. and Patil , K. B.Structure and occurrence of unusual fatty acids in minor seed oils . Prog. Lipid Res. , 19 , 119 – 153 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 26.Dhar , P. , Ghosh , S. and Bhattacharyya , D. K.Dietary effects of conjugated octadecatrienoic fatty acid (9cis, 11trans, 13trans) levels on blood lipids and nonenzymatic in vitro lipid peroxidation in rats . Lipids , 34 , 109 – 114 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 27.Takagi , T. and Itabashi , Y.Occurrence of mixtures of geometrical isomers of conjugated octadecatrienoic acid in some seed oils: analysis by open‐tubular gas liquid chromatography and high performance liquid chromatography . Lipids , 16 , 546 – 551 ( 1981. ). [Google Scholar]
  • 28.Suzuki , R. , Noguchi , R. , Ota , T. , Abe , M. , Miyashita , K. and Kawada , T.Cytotoxic effect conjugated trienoic fatty acids on mouse tumor and human monocytic leukemia cells . Lipids , 36 , 477 – 482 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 29.Kohno , H. , Maeda , M. , Honjo , S. , Murakami , M. , Shimada , R. , Masuda , S. , Simuda , T. , Azuma , Y. , Ogawa , H. and Tanaka , T.Prevention of colonic preneoplastic lesions by the β‐cryptoxanthin and hesperidin rich powder prepared from Citrus unshiu Marc. juice in male F344 rats . J. Toxicol. Pathol , 12 , 209 – 215 ( 1999. ). [Google Scholar]
  • 30.Pereira , M. A.Prevention of colon cancer and modulation of aberrant crypt foci, cell proliferation, and apoptosis by retinoids and NSAIDs . Adv. Exp. Med. Biol. , 470 , 55 – 63 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 31.Folch , J. , Lees , M. and Stanley , G. H. S.A simple method for the isolation and purification of total lipids from animal tissues . J. Biol. Chem. , 226 , 497 – 509 ( 1957. ). [PubMed] [Google Scholar]
  • 32.American Institute of Nutrition . Report of the American Institute of Nutrition ad hoc Committee on Standards for Nutritional Studies . J. Nutr. , 107 , 1340 – 1348 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 33.Tanaka , T. , Kawabata , K. , Makita , H. , Kakumoto , M. , Satoh , K. , Hara , A. and Mori , H.Citrus auraptene inhibits chemically induced colonic aberrant crypt foci in male F344 rats . Carcinogenesis , 18 , 2155 – 2161 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 34.Kerr , J. F. , Gobe , G. C. , Winterford , C. M. and Harmon , B. V.Anatomical methods in cell death . Methods Cell Biol. , 46 , 1 – 27 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 35.Kramer , J. K. G. , Sehat , N. , Fritsche , J. , Mossoba , M. M. , Eulitz , K. , Yurawecz , M. P. and Ku , Y.Separation of conjugated fatty acid isomers . In “ Advances in Conjugated Linoleic Acid Research ,” ed. Yurawecz M. P. , Mossoba M. M. , Kramer J. K. G. , Pariza M. W. and Nelson G. J. , pp. 64 – 82 ( 1999. ). AOCS Press; , Champaign , IL . [Google Scholar]
  • 36.Sehat , N. , Kramer , J. K. G. , Mossoba , M. M. , Yurawecz , M. P. , Roach , J. A. G. , Eulitz , K. , Morehouse , K. M. and Ku , Y.Identification of conjugated linoleic acid isomers in cheese by gas chromatography, silver ion high performance liquid chromatography and mass spectral reconstructed ion profiles. Comparison of chromatographic elution sequences . Lipids , 33 , 963 – 971 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 37.McLellan , E. , Medline , A. and Bird , R. P.Sequential analysis of the growth and morphological characteristics of aberrant crypt foci: putative preneoplastic lesions . Cancer Res. , 51 , 5270 – 5274 ( 1991. ). [PubMed] [Google Scholar]
  • 38.Pretlow , T. P. , O'Riordan , M. A. , Somich , G. A. , Amini , S. B. and Pretlow , T. G.Aberrant crypts correlate with tumor incidence in F344 rats treated with azoxymethane and phytate . Carcinogenesis , 13 , 1509 – 1512 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 39.Hart , R. W. and Turturro , A.Dietary restrictions and cancer . Environ. Health Perspect. , 105 ( Suppl. 4 ), 989 – 992 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Belury , M. A. and Kempa‐Steczko , A.Conjugated linoleic acid modulates hepatic lipid composition in mice . Lipids , 32 , 199 – 204 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 41.Xu , M. and Dashwood , R. H.Chemoprevention studies of heterocyclic amine‐induced colon carcinogenesis . Cancer Lett. , 143 , 179 – 183 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 42.Zheng , Y. , Kramer , P. M. , Olson , G. , Lubet , R. A. , Steele , V. E. , Kelloff , G. J. and Pereira , M. A.Prevention by retinoids of azoxymethane‐induced tumors and aberrant crypt foci and their modulation of cell proliferation in the colon of rats . Carcinogenesis , 18 , 2119 – 2125 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 43.Tanaka , T. , Shimizu , M. , Kohno , H. , Yoshitani , S. , Tsukio , Y. , Murakami , A. , Safitri , R. , Takahashi , D. , Yamamoto , K. , Koshimizu , K. , Ohigashi , H. and Mori , H.Chemoprevention of azoxymethane‐induced rat aberrant crypt foci by dietary zerumbone isolated from Zingiber zerumbet . Life Sci. , 69 , 1935 – 1945 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 44.Tanaka , T. , Kohno , H. , Shimada , R. , Kagami , S. , Yamaguchi , F. , Kataoka , S. , Ariga , T. , Murakami , A. , Koshimizu , K. and Ohigashi , H.Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats . Carcinogenesis , 21 , 1183 – 1189 ( 2000. ). [PubMed] [Google Scholar]
  • 45.Cohen , S. M.Cell proliferation and carcinogenesis . Drug Metab. Rev. , 30 , 339 – 357 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 46.Frstenberger , G. and Marks , F.Early prostaglandin E synthesis is an obligatory event in the induction of cell proliferation in mouse epidermis in vivo by the phorbol ester TPA . Biochem. Biophys. Res. Commun. , 92 , 749 – 756 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 47.Ha , Y. L. , Grimm , N. K. and Pariza , M. W.Anticarcinogens from fried ground beef: heat‐altered derivatives of linoleic acid . Carcinogenesis , 8 , 1881 – 1887 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 48.Ha , Y. L. , Storkson , J. and Pariza , M. W.Inhibition of benzo(a)pyrene‐induced mouse forestomach neoplasia by conjugated dienoic derivatives of linoleic acids . Cancer Res. , 50 , 1097 – 1101 ( 1990. ). [PubMed] [Google Scholar]
  • 49.Ip , C. , Singh , M. , Thompson , H. J. and Scimeca , J. A.Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat . Cancer Res. , 54 , 1212 – 1215 ( 1994. ). [PubMed] [Google Scholar]
  • 50.Schonberg , S. and Krokan , H. E.The inhibitory effect of conjugated dienoic derivatives (CLA) of linoleic acid on the growth of human tumor cell lines is in part due to increased lipid peroxidation . Anticancer Res. , 15 , 1241 – 1246 ( 1995. ). [PubMed] [Google Scholar]
  • 51.Shultz , T. D. , Chew , B. P. , Seaman , W. R. and Luedecke , L. O.Inhibitory effect of conjugated dienoic derivatives of linoleic acid and β‐carotene on the in vitro growth of human cancer cells . Cancer Lett , 63 , 125 – 133 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 52.Belury , M. A.Conjugated dienoic linoleate: a polyunsaturated fatty acid with unique chemoprotective properties . Nu.tr. Rev. , 53 , 83 – 89 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 53.Moya‐Camarena , S. Y. , Vanden Heuvel , J. P. and Belury , M. A.Conjugated linoleic acid activates peroxisome proliferator‐activated receptor α and β subtypes but does not induce hepatic peroxisome proliferation in Sprague‐Dawley rats . Biochim. Biophys. Acta , 1436 , 331 – 342 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 54.McCarty , M. F.Activation of PPARgamma may mediate a portion of the anticancer activity of conjugated linoleic acid . Med. Hypotheses , 55 , 187 – 188 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 55.Houseknecht , K. L. , Vanden Heuvel , J. P. , Moya‐Camarena , S. Y. , Portocarrero , C. P. , Peck , L. W. , Nickel , K. P. and Belury , M. A.Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat . Biochem. Biophys. Res. Commun. , 244 , 678 – 682 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 56.Moya‐Camarena , S. Y. , Vanden Heuvel , J. P. , Blanchard , S. G. , Leesnitzer , L. A. and Belury , M. A.Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARα . J. Lipid Res. , 40 , 1426 – 1433 ( 1999. ). [PubMed] [Google Scholar]
  • 57.Tanaka , T. , Kohno , H. , Yoshitani , S. , Takashima , S. , Okumura , A. , Murakami , A. and Hosokawa , M.Ligands for peroxisome proliferator‐activated receptors α and γ inhibit chemically induced colitis and formation of aberrant crypt foci in rats . Cancer Res. , 61 , 2424 – 2428 ( 2001. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES