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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 Aug;87(8):798–804. doi: 10.1111/j.1349-7006.1996.tb02103.x

Chemoprevention by Pravastatin, a 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A Reductase Inhibitor, of N‐Methyl‐N‐nitrosourea‐induced Colon Carcinogenesis in F344 Rats

Tomio Narisawa 1,✉, Masami Morotomi 2, Yoko Fukaura 1, Makiko Hasebe 1, Michiko Ito 1, Rika Aizawa 1
PMCID: PMC5921171  PMID: 8797885

Abstract

A potential chemopreventive action of pravastatin (Pr), a 3‐hydroxy‐3‐methylglutaryl‐coenzyme A redutase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an intrarectal dose of 2 mg of N‐methyl‐N‐nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in experiment II (4 groups of 30 rats each). They were given drinking water containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in experiment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of colon carcinomas at termination of the experiment at week 40 was not different in the 200 ppm Pr and control groups in experiment I (63% vs. 69%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in experiment II (50%, 48%, and 77% vs. 80%). This inhibitory effect of Pr against colon carcinogenesis was not related to the cholesterol‐lowering effect of this agent. We postulate that Pr inhibits the promotion stage of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth‐regulating proteins such as p21 ras.

Keywords: Colon cancer, Cancer chemoprevention, Pravastatin, HMG‐CoA reductase

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REFERENCE

  • 1.Quesney‐Huneeus , V. , Wiley , M. H. and Siperstein , M. D.Essential role for mevalonate synthesis in DNA replication . Proc. Natl. Acad. Sci. USA , 76 , 5056 – 5060 ( 1979. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Casey , P. J. , Solski , P. A. , Der , C. J. and Buss , T. E.p21 ras is modified by a farnesyl isoprenoid . Proc. Natl. Acad. Sci. USA , 86 , 8323 – 8327 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Schafer , W. R. , Kim , R. , Sterne , R. , Thorner , J. , Kim , S.‐H. and Rine , J.Genetic and pharmacological suppression of oncogenic mutations in RAS genes of yeast and humans . Science , 245 , 379 – 385 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 4.Goldstein , J. L. and Brown , M. S.Regulation of the mevalonate pathway . Nature , 343 , 425 – 430 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5.Bennis , F. , Favre , G. , Gaillard , F. L. and Soula , G.Importance of mevalonate‐derived products in the control of HMG‐CoA reductase activity and growth of human lung adenocarcinoma cell line A549 . Int. J. Cancer , 55 , 640 – 645 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 6.Feleszko , W. , Lasek , W. , Golab , J. and Jakobisiak , M.Synergistic antitumor activity of tumor necrosis factor α and lovastatin against MmB16 melanoma in mice . Neoplasma , 42 , 69 – 74 ( 1995. ). [PubMed] [Google Scholar]
  • 7.Goldstein , J. L. , Helgesen , J. A. and Brown , M. S.Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor . J. Biol. Chem ., 254 , 5403 – 5409 ( 1979. ). [PubMed] [Google Scholar]
  • 8.Kawata , S. , Kakimoto , H. , Ishiguro , H. , Yamasaki , E. , Inui , Y. and Matsuzawa , Y.Effect of pravastatin, a potent 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitor, on survival of AH130 hepatoma‐bearing rats . Jpn. J. Cancer Res ., 83 , 1120 – 1123 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Maltese , W. A. , Defedini , R. , Green , R. A. , Sheridan , K. M. and Donley , D. K.Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase . J. Clin. Invest ., 76 , 1748 – 1754 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Newman , A. , Clutterbuck , R. D. , Powles , R. L. and Miller , J. L.Selective inhibition of primary acute myeloid leukemia cell growth by lovastatin . Leukemia , 8 , 274 – 280 ( 1994. ). [PubMed] [Google Scholar]
  • 11.Sinensky , M. , Beck , L. A. , Leonard , S. and Evans , R.Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis . J. Biol. Chem ., 265 , 19937 – 19941 ( 1990. ). [PubMed] [Google Scholar]
  • 12.Soma , M. R. , Baetta , R. , Renzis , R. , Mazzini , G. , Davegna , C. , Magrassi , L. , Butti , G. , Pezzotta , S. , Paoletti , R. and Fumagalli , R.In vivo enhanced antitumor activity of carmustin [N, N'‐bis (2‐chloroethyl)‐N‐nitrosourea] by simvastatin . Cancer Res ., 55 , 597 – 602 ( 1995. ). [PubMed] [Google Scholar]
  • 13.Sumi , S. , Beauchamp , D. , Townsend , C. M. , Jr. , Uchida , T. , Murakami , M. , Rajaraman , S. , Ishizuka , T. and Thompson , J.Inhibition of pancreatic adenocarcinoma cell growth of lovastatin . Gastroenterology , 103 , 982 – 989 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 14.Ura , H. , Obara , T. , Nishino , N. , Tanno , S. , Okamura , K. and Namiki , M.Cytotoxicity of simvastatin to pancreatic adenocarcinoma cells containing mutant ras gene . Jpn. J. Cancer Res ., 85 , 633 – 638 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Rush , R. J. , Madhukar , B. V. , Trosko , J. E. and Klauning , J. E.Reversal of ras‐induced inhibition of gap‐junctional intercellular communication, transformation, and tumorigenesis by lovastatin . Mol. Carcinog ., 7 , 50 – 59 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 16.Sebti , S. M. , Thalcevic , G. T. and Jani , J. P.Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H‐ras oncogene transformed cells in nude mice . Cancer Commun ., 3 , 141 – 147 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17.Brown , M. S. , Faust , J. R. , Goldstein , J. L. , Kaneko , I. and Endo , A.Induction of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML‐236B), a competitive inhibitor of the reductase . J. Biol. Chem ., 253 , 1121 – 1128 ( 1978. ). [PubMed] [Google Scholar]
  • 18.Habenicht , A. J. R. , Glomset , A. J. and Russell , R.Relation of cholesterol and mevalonic acid to the cell cycle in smooth muscle and Swiss 3T3 cells stimulated to divide by platelet‐derived growth factor . J. Biol. Chem ., 255 , 5134 – 5140 ( 1980. ). [PubMed] [Google Scholar]
  • 19.Kaneko , I. , Hazama‐Shimada , Y. and Endo , A.Inhibitory effects on lipid metabolism in cultured cells of ML‐236B, a potent inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A reductase . Eur. J. Biochem ., 87 , 313 – 321 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 20.McGuire , T. F. , Corey , S. J. and Sebti , S. M.Lovastatin inhibits platelet‐derived growth factor (PDGF) stimulation of phosphatidylinositol 3‐kinase activity as well as association of p85 subunit to tyrosine‐phosphorylated PDGF receptor . J. Biol. Chem ., 268 , 2227 – 2230 ( 1993. ). [PubMed] [Google Scholar]
  • 21.Narisawa , T. , Fukaura , Y. , Terada , K. , Umezawa , A. , Tanida , N. , Yazawa , K. and Ishikawa , C.Prevention of 1,2‐dimethylhydrazine‐induced colon tumorigenesis by HMG‐CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice . Carcinogenesis , 15 , 2045 – 2048 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 22.Narisawa , T. , Sato , T. , Hayakawa , M. , Sakuma , A. , Nakano , H.Carcinoma of the colon and rectum of rats by rectal infusion of N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Gann , 62 , 231 – 234 ( 1971. ). [PubMed] [Google Scholar]
  • 23.Takahashi , T. and Morotomi , M.Absence of cholic acid 7α‐dehydroxylase activity in the strains of Lactobacillus and Bifidobacterium. J. Dairy Sci ., 77 , 3275 – 3286 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 24.van Faassen , A. , Bol , J. , van Dokkum , W. , Pikaar , N. A. , Ockhuizen , T. and Hermus , R. J. J.Bile acids, neutral sterols, and bacteria in feces as affected by a mixed, a lacto‐ovovegetarian, and a vegan diet . Am. J. Clin. Nutr ., 46 , 962 – 967 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 25.Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 26.Jacoby , R. F. , Llor , X. , Teng , B. B. , Davidson , N. O. and Brasitus , T. A.Mutations in the k‐ras oncogene induced by 1,2‐dimethylhydrazine in preneoplastic and neoplastic rat colonic mucosa . J. Clin. Invest ., 87 , 624 – 630 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Jacoby , R. F. , Alexander , R. J. , Raicht , R. F. and Brasitus , T. A.K‐ras oncogene mutations in rat colon tumors induced by N‐methyl‐N‐nitrosouea . Carcinogenesis , 13 , 45 – 49 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 28.Pretlow , T. P. , Brasitus , T. A. , Fulton , N. C. , Cheyer , C. and Kaplan , E. L.K‐ras mutations in putative preneoplastic lesions in human colon . J. Natl. Cancer Inst ., 85 , 2004 – 2007 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 29.Stopera , S. A. , Murphy , L. C. and Bird , R. P.Evidence for a ras gene mutation in azoxymethane‐induced colonic aberrant crypts in Spague‐Dawley rats: earliest recognizable precursor lesions of experimental colon cancer . Carcinogenesis , 13 , 2081 – 2085 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 30.Crowell , P. L. , Ren , Z. , Lin , S. , Wedejs , E. and Gould , M. N.Structure‐activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation . Biochem. Pharmacol ., 47 , 1405 – 1415 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 31.James , G. L. , Goldstein , J. L. , Brown , M. S. , Rawson , T. E. , Somers , T. C. , McDowell , R. S. , Crowley , C. W. , Lucas , B. K. , Levinson , A. D. and Marsters , J. C. , Jr.Benzodiazepine peptidomimetics: potent inhibitors of ras farnesylation in animal cells . Science , 260 , 1937 – 1942 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 32.Nagasu , T. , Yoshimatsu , K. , Rowell , C. , Lewis , M. D. and Garcia , A. M.Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956 . Cancer Res ., 55 , 5310 – 5314 ( 1995. ). [PubMed] [Google Scholar]
  • 33.Sepp‐Lorenzino , L. , Ma , Z. , Rands , E. , Kohl , N. E. , Gibbs , J. B. , Oliff , A. and Rosen , N.A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchor‐age‐dependent and ‐independent growth of human tumor cell lines . Cancer Res ., 55 , 5302 – 5309 ( 1995. ). [PubMed] [Google Scholar]
  • 34.Endo , A. , Tsujita , Y. , Kuroda , M. and Tanzawa , K.Effects of ML‐236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals . Biochim. Biophys. Acta , 575 , 266 – 276 ( 1979. ). [PubMed] [Google Scholar]
  • 35.Tsujita , Y. , Kuroda , M. , Shimada , Y. , Tanzawa , K. , Arai , M. , Kaneko , I. , Tanaka , M. , Masuda , H. , Tarumi , C. , Watanabe , Y. and Fujii , S.CS‐514, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase: tissue‐selective inhibition of sterol synthesis and hypolipidemic effect on various animal species . Biochim. Biophys. Acta , 877 , 50 – 60 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 36.Rudney , H. and Sexton , R. C.Regulation of cholesterol biosynthesis . Ann. Rev. Nutr ., 6 , 245 – 272 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 37.Fujioka , T. , Nara , F. , Tsujita , Y. , Fukushige , J. , Fukami , M. and Kuroda , M.The mechanism of lack of hypocholesterolemic effects of pravastatin sodium, a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, in rats . Biochim. Biophys. Acta , 1254 , 7 – 12 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 38.Puppo , D. M. , Rauli , S. and Kienle , G. M.Inhibition of cholesterol synthesis and hepatic 3‐hydroxy‐3‐methylglutaryl‐CoA reductase in rats by simvastatin and pravastatin . Lipids , 30 , 1057 – 1061 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 39.Narisawa , T. , Magadia , N. E. , Weisburger , J. H. and Wynder , E. L.Promoting effect of bile acids in colon carcinogenesis after intrarectal instillation of N‐methyl‐N'‐nitro‐N‐nitrosoguanidine in rats . J. Natl. Cancer Inst ., 53 , 1093 – 1097 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 40.Reddy , B. S. , Watanabe , K. , Weisburger , J. H. and Wynder , E. L.Promoting effect of bile acids in colon carcinogenesis in germ‐free and conventional F344 rats . Cancer Res ., 37 , 3238 – 3242 ( 1977. ). [PubMed] [Google Scholar]
  • 41.Khan , S. G. , Saxena , R. , Bickers , D. R. , Mukhtar , H. and Agarwal , R.Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen‐induced murine skin tumors by lovastatin . Mol. Carcinog ., 12 , 205 – 212 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 42.Siperstein , M. D. and Fagan , V. M.Deletion of cholesterol‐negative feedback system in liver tumors . Cancer Res ., 24 , 1108 – 1115 ( 1964. ). [PubMed] [Google Scholar]
  • 43.Goldfarber , S. and Pitot , H. C.The regulation of β‐hydroxy‐β‐methylglutaryl coenzyme A reductase in Morris hepatomas 5123C, 7800, and 9618A . Cancer Res ., 31 , 1879 – 1882 ( 1971. ). [PubMed] [Google Scholar]

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