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Monoterpenes as Regulators of Malignant Cell Proliferation

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Dietary Phytochemicals in Cancer Prevention and Treatment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 401))

Abstract

Limonene and related monoterpenes display compelling anticarcinogenic activity. The mechanism(s) that underlie this activity is/are as yet unknown. One attractive possibility is that the monoterpenes interact with the RAS signal transduction pathway. The monoterpenes have been shown to impair incorporation of mevalonic acid-derived isoprene compounds, that is farnesyl pyrophosphate, into RAS and RAS-related proteins. As farnesylation is critical for RAS’s membrane localization and function, the isoprenylation pathways have received attention as potential targets of anti-RAS pharmacological maneuvers. We have expanded on prior studies and demonstrate that one of limonene’s metabolic derivatives, perillyl alcohol, decreases the levels of antigenic RAS in the human-derived myeloid THP-1 and lymphoid RPMI-8402 leukemia cell lines. Both limonene and perillyl alcohol decrease levels of 35[S]-methionine labeled RAS proteins in cells that have been pulsed with radiolabeled methionine for four hours. In contrast, lovastatin, which inhibits hydroxymethylglutaryl coenzyme A reductase and thus depletes cells of farnesyl pyrophosphate, does not diminish levels of total antigenic RAS but rather results in a shift in the RAS protein; levels of farnesylated RAS decrease whereas levels of unmodified/unfarnesylated RAS increase. As limonene and perillyl alcohol do not induce such a shift we conclude that these monoterpenes decrease farnesylated RAS protein levels by a mechanism that is clearly distinct from that of either depleting cells of farnesyl pyrophosphate or inhibiting the enzyme farnesyl protein transferase that catalyzes the posttranslational farnesylation of RAS. These findings are discussed with respect to implications for the monoterpenes to alter RAS protein synthesis and degradation. The results of these studies will likely impact the inclusion of the monoterpenes in clinical anticancer trials.

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References

  1. Igimi, H., Hisatsuga, T., and Nishimura M. The use of d-limonene as a dissolving agent in gallstones. Dig. Dis., 21: 926–939, 1976.

    Article  CAS  Google Scholar 

  2. Elegbede, J. A., Elson, C. E., Qureshi, A., Tanner, M. A., and Gould, M. N. Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene. Carcinogenesis, 5: 661–664, 1984.

    Article  CAS  Google Scholar 

  3. Elegbede, J. A., Elson, C. E., Tanner, M. A., Qureshi, A. and Gould, M. N. Regression of rat primary mammary tumors following dietary d-limonene. J. Natl. Cancer Inst., 76: 323–325, 1986.

    CAS  Google Scholar 

  4. Elson, C. E., Maltzman, T. H., Boston, J. L., Tanner, M. A., and Gould, M. N. Anti-carcinogenic activity of d-limonene during the initiation and promotion/progression stages of DMBA-induced rat mammary carcinogenesis. Carcinogenesis, 9: 331–332, 1988.

    Article  CAS  Google Scholar 

  5. Maltzman, T. H., Hurt, L. M., Elson, C. E., Tanner, M. A., and Gould M. N. The prevention of nitrosomethylurea-induced mammary tumors by d-limonene and orange oil. Carcinogenesis, 10: 781–783, 1989.

    Article  CAS  Google Scholar 

  6. Wattenberg, L. W., Sparnns, V. L., and Barany, G. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occuring organosulfu compounds and monoterpees. Cancer Res., 49: 2689-2692, 1989.

    CAS  Google Scholar 

  7. Lin, F. K., Banerjee, M. R., and Cump, L. R. Cell cycle related hormone carcinogen interaction during chemical carcinogen induction of nodule-like mammary lesions in organ culture. Cancer Res., 36: 1607–1614, 1976.

    CAS  Google Scholar 

  8. Mehta, R. G., and Moon, R. C. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol. Anticancer Res., 11: 593–596, 1991.

    CAS  Google Scholar 

  9. Russin, W. A., Hoesly, J. D., Elson, C. E., Tanner, M. A., and Gould M. N. Inhibition of rat mammary carcinogenesis by monoterpenoids. Carcinogenesis, 10: 2161–2164, 1989.

    Article  CAS  Google Scholar 

  10. Steele, V. E., Kelloff, G. J., Wilkinson, B.R, and Arnold, J. T. Inhibition of transformation in cultured rat tracheal epithelial cells by potential chemopreventive agents. Cancer Res., 50: 2068–2074, 1990.

    CAS  Google Scholar 

  11. Kodama, R., Yano, T., Furukawa, K., Noda, K. and Ide, H. Studies on the metabolism of d-limonene (p-mentha-l,8-diene). IV Isolation and characterization of new metabolites and species differences in metabolism. Xenobiotica, 6: 377–389, 1976.

    Article  CAS  Google Scholar 

  12. Crowell, P. L., Lin, S., Vedejs, E., and Gould, M. N. Identification of circulating metabolites of the antitumor agent d-limonene capable of inhibiting protein isoprenylation and cell growth. Cancer Chemother Pharmacol 31: 205–212, 1992.

    Article  CAS  Google Scholar 

  13. Crowell, P. L, Elson C. E., Bailey, H. H., Elegbede, A., Haag, J. D., and Gould, M. N. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 35: 31–37, 1994.

    Article  CAS  Google Scholar 

  14. Crowell, P. J., Ren, Z., Lin, S., Vedejs, E., and Gould, M. N. Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. Biochem Pharmacol 47: 1405–1415, 1994.

    Article  CAS  Google Scholar 

  15. Ruch, R. J. and Sigler, K. Growth inhibition of rat liver epithelial tumor cells does not involve RAS plasma membrane association. Carcinogenesis 15: 787–789, 1994.

    Article  CAS  Google Scholar 

  16. Schulz, S., Buhling, F., and Ansorge, S. Prenylated proteins and lymphocyte proliferation: inhibition by d-limonene and related monoterpenes. Eur J Immunol 24: 301–301, 1994.

    Article  CAS  Google Scholar 

  17. Bronfen, J. H., Stark, J. M., and Crowell, P. L. Inhibition of human pancreatic carcinoma cell proliferation by perillyl alcohol. Proc Am. Assoc. Cancer Res. 35: 431, 1994. (abstr.)

    Google Scholar 

  18. Hohl, R. J. and Lewis, K. RAS expression in human leukemia is modulated differently by lovastatin and limonene. Blood 80: 299a, 1992. (abstr.)

    Google Scholar 

  19. Barbacid, M. RAS Genes. Ann. Rev. Biochem, 56: 779–827, 1987.

    Article  CAS  Google Scholar 

  20. Bos, J. L. RAS Oncogenes in Human Cancer: A Review. Cancer Res., 49: 4682–4689, 1989.

    CAS  Google Scholar 

  21. Kitayama, H., Sugimoto, Y., Matsuzak, T., Ikawa, Y, and Noda, M. A ras-related gene with transformation supressor activity. Cell, 56: 77–84, 1989.

    Article  CAS  Google Scholar 

  22. Chang, E. H., Furth, M. E., Scolnick, E. M. and Lowy, D. R. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature, 297:478–483, 1982.

    Article  Google Scholar 

  23. Chin, K. V, Ueda, K., Pastan, I., and Gottesman, M. M, Modulation of activity of the promoter of the human MDR1 gene by ras and p53. Science, 255: 459–462, 1992.

    Article  CAS  Google Scholar 

  24. Schafer, W. R., Kim, R., Sterne, R., Thorner, J., Kim, S-H., and Rine, J. Genetic and pharmacologic supression of oncogenic mutations in RAS genes of yeast and humans. Science, 245: 379–385, 1989.

    Article  CAS  Google Scholar 

  25. 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: 1167–1177, 1989.

    Article  CAS  Google Scholar 

  26. Willumsen, B. M., Norris, K., Papageorge, A. G., Hubbert, N. L. and Lowy, D. L. Harvey murine sarcoma virus p21 ras protein:biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J., 3: 2581–2585, 1984.

    CAS  Google Scholar 

  27. Endo, A., Kuroda, M., and Tsujita, Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterol-genesis produced by Penicillium citrinum. J. Antibiot., 24: 1346–1348, 1976.

    Google Scholar 

  28. Hohl, R. J., Mannickarottu, V, and Yachnin, S. The effect of alterations of hydroxymethylglutaryl coenzyme A eductase on the expression of the RAS oncogene. Clinical Research. 38: 843 A. 1990. (abstr.)

    Google Scholar 

  29. Hohl, R. J., Larson, R. A., Mannickarottu, V. and Yachnin, S. Inhibition of hydroxymethylglutaryl coenzyme A reductase activity induces a paradoxical increase in DNA synthesis in myeloid leukemia cells. Blood, 77: 1064–1070, 1991,

    Google Scholar 

  30. Reiss, Y, Goldstein, J.L., Seabra, M. C., Casey, P.J., and Brown, M.S. Inhibition of purified p21ras farnesyl; protein transferase by Cys-AAX tetrapeptides. Cell 62: 81–86, 1990.

    Article  CAS  Google Scholar 

  31. Gibbs, J., Pompliano, D., Mosser, S., Rands, E., Lingham, R., Singh S., Scolnick, E, Kohl, N., and Oliff, A. Selective inhibition of farensyl-protein transferase blocks ras processing in vivo. J Biol Chem 268: 7617–7620, 1993.

    CAS  Google Scholar 

  32. Kohl, N., Mosser, S., deSolms, S., Giuliani, E., Pompliano, D., Graham, S., Smith, R., Scolnick, E., Oliff, A., and Gibbs, J. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260: 1934–1937, 1993.

    Article  CAS  Google Scholar 

  33. James, G., Goldstein, J., Brown, M., Rawson, T., Somers, T., McDowell, R., Crowley, C, Lucas, B., Levinson, A., and Marsters, J. Benzodiazepine peptidomimetics: potent inhibitors of ras farnesylation in animal cells. Science 260: 1937–1941, 1993.

    Article  CAS  Google Scholar 

  34. Garcia, A. M., Rowell, C, Ackerman, K., Kowalczyk, J. J., and Lewis, M. D. Peptidomimetic inhibitors of ras farnesylation and function in whole cells. J Biol Chem 268: 18415–18418, 1993.

    CAS  Google Scholar 

  35. Nigam, M., Seong, C, Qian, Y., Hamilton, A., and Sebti, S. Potent inhibition of human tumor p21ras farensyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics. J Biol Chem 268: 20695–20698, 1993.

    CAS  Google Scholar 

  36. 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.

    CAS  Google Scholar 

  37. Clegg, R. J., Middleton, B., Bell, C. D., and White, D. A. The mechanism of cyclic monoterpene inhibition of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase in vivo in the rat. J Biol Chem 257: 2294–2299, 1982.

    CAS  Google Scholar 

  38. Jirtle, R. L., Haag, J. D., Ariazi, E. A., and Gould, M.N. Increased mannose 6-phosphate/insulin-like growth factor II receptor and transforming growth factor ß1 levels during monoterpene-induced regression of mammary tumors. Cancer Res 53: 3849–3852, 1993.

    CAS  Google Scholar 

  39. Schmidt, R. A., Schneider, C. J., and 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.

    CAS  Google Scholar 

  40. Ulsh, L. S., and Shih, T. Y. Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs. Mol Cell Biol 4: 1647–1652, 1984.

    CAS  Google Scholar 

  41. Hohl, R. J., and Lewis K. Differential effects of monoterpenes and lovastatin on RAS processing. J Biol Chem 270: 17508–17512, 1995.

    Article  CAS  Google Scholar 

  42. Kawata, S., Nagase, T., Yamasaki, E., Ishiguro, H., and Matsuzwawa, Y Modulation of the mevalonate pathway and cell growth by pravastatin and d-limonene in a human hepatoma cell line (Hep G2). Br J Cancer 69: 1015–1020, 1994.

    Article  CAS  Google Scholar 

  43. Raj, M., Kratz, D., Lewis, K., and Hohl, R. J. Effects of combinations of lovastatin and monoterpenes on ras processing. Proc of AACR 36: 428, 1995. (abstr.)

    Google Scholar 

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  1. Departments of Internal Medicine and Pharmacology, University of Iowa, Iowa City, Iowa, 52242, USA

    Raymond J. Hohl

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    © 1996 Plenum Press, New York

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    Hohl, R.J. (1996). Monoterpenes as Regulators of Malignant Cell Proliferation. In: Dietary Phytochemicals in Cancer Prevention and Treatment. Advances in Experimental Medicine and Biology, vol 401. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0399-2_11

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    • DOI: https://doi.org/10.1007/978-1-4613-0399-2_11

    • Publisher Name: Springer, Boston, MA

    • Print ISBN: 978-1-4613-8034-4

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