Advertisement

Effects of Monoterpenes and Mevinolin on Murine Colon Tumor CT-26 in Vitro and its Hepatic “Metastases” in Vitro

  • Selwyn A. Broitman
  • John WilkinsonIV
  • Sonia Cerda
  • Steven K. Branch
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 401)

Abstract

d-Limonene is a monocyclic monoterpene which has been used for many years as a flavoring, perfuming, or degreasing agent. Recently, this product and its biologic metabolites have been highlighted for their chemotherapeutic potential in the management of certain common malignant diseases. Some of its metabolic actions interfere with certain aspects of cholesterol metabolism which are vital to the malignant cell and hopefully less critical to the normal cell. The mammalian cell has, as a major component of its plasma membrane, cholesterol which helps to maintain the integrity of the cell, and modulates the fluidity of the cellular lipid membrane. It thus serves as a major regulatory agent for chemical signals sent from other cells, transport of critical metabolites in and out of the cell, and for the membrane association of receptors, enzymes, and a wide variety of proteins which serve to regulate the intracellular processes of the cell.1

Keywords

Cholesterol Synthesis Colon Tumor CT26 Cell Colon Tumor Cell Perillyl Alcohol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations used

ACAT

acylCoA:cholesterol-acyl-transferase

FBS

fetal bovine serum

HMG CoA reductase

3-hydroxy-3-methylglutaryl Coenzyme A reductase

25-OH-CH

25-hydroxycholesterol

LDL

low density lipoprotein

LDLR

LDL receptor

LPDS

lipoprotein deficient serum

MEV

Mevinolin

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chen H. W. Role of cholesterol metabolism in cell growth. Fed. Proc. 43(1); 126–130, (1984).Google Scholar
  2. 2.
    Brown, M. S., and Goldstein, J. L. A receptor mediated pathway for endocytosis. Science, 232: 34–47, (1986).CrossRefGoogle Scholar
  3. 3.
    Brown, M. S. and Goldstein, J. L. Regulation of the mevalonate pathway. Nature 343: 425–430, (1990).CrossRefGoogle Scholar
  4. 4.
    Fabricant, M. and Broitman, S. A. Evidence for deficiency of low density lipoprotein receptors on human colonic carcinoma cell lines. Cancer Res. 50, 632–636, (1990).Google Scholar
  5. 5.
    Kamiya, Y., Sakurai, A., Tamura, S., Takahashi, N., Abe, K., Tsuchiga, E., Fakai, S., Kitada, C, and Fujino, M. Structure of rodotorucien A novel lipopeptide inducing mating tube formation in Rhodosporidium toruloides. Biochem. Biophys. Res. Commun. 83: 1077–1083, (1978).CrossRefGoogle Scholar
  6. 6.
    Sakagami, Y, Yoshida, M., Isogai, A., Suzuki, A. Peptidal sex hormones inducing conjugation tube formation in compatible mating-type cells of Tremella mesenterica. Science 212: 1525–1527, (1981).CrossRefGoogle Scholar
  7. 7.
    Schmidt, R. A., Schneider, C. J., Glomset, J. A. Evidence for post-translational incorporation of a product of mevalonic acid into Swiss 3T3 cell proteins. J. Biol. Chem. 259: 10175–10180, (1984).Google Scholar
  8. 8.
    Beck, L. A., Hosick, T. J. and Sinensky, M. Incorporation of a product of mevalonic acid metabolism into proteins of Chinese hamster ovary cell nuclei. J. Cell Biol. 107: 1307–1316, (1988).CrossRefGoogle Scholar
  9. 9.
    P. J. Casey. Protein lipidation in cell signaling. Science 268: 221–224, (1995)CrossRefGoogle Scholar
  10. 10.
    Marshall, C. J. Protein prenylation: a mediator of protein-protein interaction. Science 259: 1865–1866, (1993).CrossRefGoogle Scholar
  11. 11.
    Sinesky, M., Fantle, K., Trujillo, M. A., McLain, T. M., Kupfer, A., and Dalton, M. The processing pathway of prelamin a. J. Cell. Sci. 107: 61–67, (1994).Google Scholar
  12. 12.
    Wolda, S. L. and Glomset, J. A. Evidence for modification of lamin B by a product of mevalonic acid. J. Biol. Chem. 263: 5997–6000, (1988).Google Scholar
  13. 13.
    Hancock, J. S., Kadwallader, K. and Marshal, C. J. Methylation and proteolysis are essential for efficient membrane binding of prenylated p25k-ras(b). E.M.B.O. J. 10: 641–646, (1991).Google Scholar
  14. 14.
    Dalton, M. B., Fantle, K. S., Bechtold, H. A., DeMaio, L., Evans, R. M., Krystosek, A. and Sinensky, M. The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization. Cancer Res. 55: 3295–3304, (1995).Google Scholar
  15. 15.
    Grunler, J., Ericsson, J., Daliner, G. Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins. Biochim. Biophys. Acta 1212: 259–277, (1994).Google Scholar
  16. 16.
    Hancock, J. F., Magee, A. I., Childs, J. E., and Marshall, C. J.. All ras proteins are polyisoprenylated but only some are palmitoylated.. Cell 57: 11167–11177, (1989).CrossRefGoogle Scholar
  17. 17.
    Casey, P. J., Solski, P. A., Der, C. J., and Bus, J. E.. p21ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. USA 86: 8323–8327, (1989).CrossRefGoogle Scholar
  18. 18.
    Sinensky, M. and Lutz, R. J. The prenylation of proteins. Bioessays 14: 25–31, (1992).CrossRefGoogle Scholar
  19. 19.
    Khosravi-Far, R., Cox, A. D., Kato, K., and Der, C. D. Protein prenylation: key to ras function and cancer intervention?. Cell Growth and Differentiation 3: 461–469, (1992).Google Scholar
  20. 20.
    Crowell, P. L., Chang, R. R., Ren, Z., Elson, C. E. and Gould, M.N. Selective inhibition of isoprenylation of 21–26 kDa proteins by the anticarcinogen d-limonene and its metabolites. J. Biol. Chem. 266: 17679–17685,(1991).Google Scholar
  21. 21.
    Jameson, C. W. Toxicology and carcinogenesis studies of d-limonene in F344/N rats and B6C3F1 mice. NIH publication # 90–2802, (1990).Google Scholar
  22. 22.
    Homburger, F., Trager, A., Boger, E. Inhibition of murine subcutaneous and intravenous benzo(rst)pentaphene carcinogenesis by sweet orange oils in d-limonene. Oncol. 25: 1–10, (1971).CrossRefGoogle Scholar
  23. 23.
    Wattenberg, L. W. Inhibition of neoplasia by minor dietary constituents. Cancer Res. (suppl) 43: 2448s–2453s, (1983).Google Scholar
  24. 24.
    Elgebede, J. A., Elson, C. E., Qureshi, A., Tanner, M. A., Gould, M. N. Inhibition of DMBA-induced mammary cancer by the nonoterpene d-limonene. Carcinogenesis 5: 661–664, (1984).CrossRefGoogle Scholar
  25. 25.
    Elgebede, J.A., Elson, C.E., Tanner, M.A., Qureshi, A., Gould, M.N. Regression of rat primary mammary tumors following dietary d-limonene. J Natl. Cancer Inst. 76: 323–325, (1986).Google Scholar
  26. 26.
    Gould, M. N., Wacker, W. D., and Maltzman, T. H. Chemoprevention and chemotherapy of mammary tumors by monoterpenoids. In: Mutagens and Carcinogens in the Diet, Pariza, M.N., Felton, J.S., Aeschbacher, H., and Sato, S., Eds. Wiley-Liss, New York (1990).Google Scholar
  27. 27.
    Broitman, S.A., Wilkinson, J. IV, and Cerda, S. Inhibitors of cholesterol/ isoprenoid pathways as potential chemotherapeutics in colon cancer. Abstract # 1075P, World Congresses Gastroenterology, Abstract # 1075P, Los Angeles, CA, (1994).Google Scholar
  28. 28.
    Cerda, S., Wilkinson, IV, J. and Broitman, S. A. Enhanced antitumor activity of lovastatin and perillyl alcohol combination in the colonic adenocarcinoma cell line SW480. Proc. Am. Assoc. Cancer Res., 35: # 1996, (1994).Google Scholar
  29. 29.
    Wilkinson, J., Cerda, S., Cerda, S. R., Branch, S. K., and Broitman, S. A. Limonene and MEV affect growth of the human colonic adenocarcinoma LS174T implanted in the livers of nude mice. Proc. Am. Assoc. Cancer Res., 36: 1776, (1995).Google Scholar
  30. 30.
    Cerda, S., Wilkinson, J. IV, and Broitman, S. A. Regulation of cholesterol synthesis in 4 colonic adenocarcinoma cell lines. Lipids (in press).Google Scholar
  31. 31.
    Repko, E. M., Maltese, W. A. Post-translational isoprenylation of cellular proteins is altered in response to mevalonate availability. J. Biol. Chem., 264: 9945–9952, (1989).Google Scholar
  32. 32.
    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 wuth compactin (ML-236B), a competitive inhibitor of the reductase. J. Biol. Chem. 253, 1121–1128. (1978)Google Scholar
  33. 33.
    Laemmli, U. K. Cleavage of structural proteins during the assembly of head of bacteriophage T4. Nature, 227: 680–685, (1970).CrossRefGoogle Scholar
  34. 34.
    Cannizzo, F., and Broitman, S. A. Postpromotional effects of dietary marine or safflower oils on large bowel or pulmonary implants of CT-26 in mice. Cancer Res., 49: 4289–4294, (1989).Google Scholar
  35. 35.
    G. C. Ness, C.E. Sample, M. Smith, L. C. Pendleton, and D. C. Eichler. Characterisitics of Rat Liver Microsomal 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase. Biochem. J. 233: 167–172, (1986).Google Scholar
  36. 36.
    D. J. Shapiro, J. L. Nordstrom, J. J. Mitschelen, V. W. Rodwell, and R. T. Schimke. Micro Assay for 3-Hydroxy-3-methylglutaryl-CoA Reductase in Rat Liver and in L-cell Fibroblasts. Biochim. Biophys. Acta 370: 369 (1974)..Google Scholar
  37. 37.
    G. C. Ness, Z. Zhao, and L. Wiggins. Insulin and Glucagon Modulate Hepatic 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Activity by Affecting Immunoreactive Protein Levels. J. Bio. Chem. 269: 29168–29172 (1994)..Google Scholar
  38. 38.
    Crowel, P. L., Ren, Zhibin, Lin, Shouzhong, Vedejs, E., Gould, M.N. Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. Biochem. Pharmacol., 47: 1405–1415, (1994).CrossRefGoogle Scholar
  39. 39.
    Crowell, P. L., Chang, R. R., Ren, Z., Elson, C. E., Gould, M. N. Selective inhibition of isoprenylation of 21–26-kDa proteins by the anticarcinogen d-limonene and its metabolites. J. Biol. Chem., 266: 17679–17685, (1991).Google Scholar
  40. 40.
    Schultz, S., Buhling, F., Ansorge, S. Prenylated proteins and lymphocyte proliferation: inhibition by d-limonene and related monoterpenes. Eur. J. Immunol. 24: 301–307, (1994).CrossRefGoogle Scholar
  41. 41.
    Hohl, R. J., and Lewis, K. Differential effects of monoterpenes and lovatstatin on ras processing. J Biol. Chem. 270: 17508–12, (1995).CrossRefGoogle Scholar
  42. 42.
    Ren, Z., Gould, M. N. Inhibition of protein isoprenylation by the monoterpene perillyl alcohol in intact cells and in cell lysates. Proc. Am. Assoc. Cancer Res., 36: 585, (1995).Google Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Selwyn A. Broitman
    • 1
  • John WilkinsonIV
    • 1
  • Sonia Cerda
    • 1
  • Steven K. Branch
    • 1
  1. 1.Departments of Microbiology, and Pathology and Laboratory MedicineBoston University School of Medicine and the Mallory Institute of PathologyBostonUSA

Personalised recommendations