Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase

Nature Medicine volume 1, pages 260–266 (1995)Cite this article

An Erratum to this article was published on 01 June 1995

This article has been updated

Abstract

For the discovery of new cancer chemopreventive agents, we have studied the potential of plant extracts to inhibit phorbol ester-induced ornithine decarboxylase (ODC) activity in cell culture. Four active rotenoids were obtained from the African plant Mundulea sericea (Leguminosae). These isolates were highly potent when evaluated for inhibition of chemically induced preneoplastic lesions in mammary organ culture and inhibition of papillomas in the two-stage mouse skin model, and they appear to function by a unique mechanism at the level of ODC messenger RNA expression. Based on our findings, rotenoids can be regarded as promising new chemopreventive or anticancer agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Change history

  • 01 June 1995

    HIV-speciflc cytotoxic T-cells in HIV-exposed but uninfected Gambian women S. Rowland-Jones, J. Sutton, K. Ariyoshi, T. Dong, F. Gotch, S. Mcadam, D. Whitby, S. Sabally, A. Gallimore, T. Corrah, M. Takiguchi, T. Schultz, Andrew Mcmichael & H. Whittle Nature Medicine 1, 59–64, 1995. An error in typography resulted in the incorrect printing of m for the Greek character μ.

References

  1. Sporn, M.B. & Newton, D.L. Chemoprevention of cancer with retinoids. Fed. Proc. 38, 2528–2534 (1979).

    CAS  PubMed  Google Scholar 

  2. Wattenberg, L.W. Chemoprevention of cancer. Cancer Res. 45, 1–8 (1985).

    Article  CAS  Google Scholar 

  3. Talaly, P. The role of enzyme induction in protection against carcinogenesis. Cancer Chemoprevention (Wattenberg, Lipkin, Boone & Kelloff eds.) 469–478 (CRC Press, Boca Raton, FL, 1992).

    Google Scholar 

  4. Kelloff, G.J. et al. Chemopreventive drug development: Perspectives and progress. Cancer Epidemiol. Biomarkers & Prev. 3, 85–98 (1994).

    CAS  Google Scholar 

  5. Szarka, C.E., Grana, G. & Engstrom, P. Chemoprevention of cancer. Curr. Probl. Cancer 18, 1–78 (1994).

    Article  Google Scholar 

  6. Boutwell, R.K. Biochemical mechanism of tumour promotion. Carcinogenesis, Vol. 2. Mechanism of Tumour Promotion and Cocarcinogenesis (Slaga, Sivak & Boutwell, eds.) 49–58 (Raven Press, New York, 1978).

    Google Scholar 

  7. Pezzuto, J.M., Cancer Chemopreventive agents: from plant materials to clinical trials. Human Medical Agents from Plants (ACS Symposium Series No. 534) (Kinghorn & Balandrin, eds.) 205–217 (American Chemical Society Books, Washington, DC, 1993).

    Chapter  Google Scholar 

  8. Pezzuto, J.M. Nalural products cancer chemopreventive agents. Recent Adv. Phytochem. 29 (in the press).

  9. Peña, A. et al. Regulation of human ornithine decarboxylase expression by the c-Myc•Max protein complex. J. biol. Chem. 268, 27277–27285 (1993).

    PubMed  Google Scholar 

  10. McCann, P.P. & Pegg, A. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol. Ther. 54, 195–215 (1992).

    Article  CAS  Google Scholar 

  11. Van Daalen Wetters, T., Brabant, M. & Coffino, P. Regulation of ornithine decarboxylase activity by cell growth, serum and tetradecanoyl phorbol acetate is governed primarily by sequences within the coding region of the gene. Nucleic Acids Res. 17, 9843–9860 (1989).

    Article  CAS  Google Scholar 

  12. Auvinen, M., Paasinen, A., Andersson, L.C. & Hölttä, E. Ornithine decarboxylase activity is critical for cell transformation. Nature 360, 355–358 (1992).

    Article  CAS  Google Scholar 

  13. Luyengi, L. et al. Rotenoids and chalcones from Mundulea sericea with ornithine decarboxylase inhibiting activity. Phytochemistry 36, 1523–1526 (1994).

    Article  CAS  Google Scholar 

  14. Verma, A.K. Inhibition of tumour promoter 12-O-tetradecanoylphorbol-13-acetate-induced synthesis of epidermal ornithine decarboxylase messenger RNA and diacylglycerol-promoted mouse skin tumour formation by retinoic acid. Cancer Res. 48, 2168–2173 (1988).

    CAS  PubMed  Google Scholar 

  15. Verma, A.K., Pong, R.-C. & Erickson, D. Involvement of protein kinase C activation in ornithine decarboxylase gene expression in primary culture of newborn mouse epidermal cells and in skin tumour promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 46, 6149–6155 (1986).

    CAS  PubMed  Google Scholar 

  16. Konoshima, T. et al. Studies on inhibitors of skin tumour promotion, XII. Rotenoids from Amorpha fruticosa . J. Nat. Prod. 56, 843–848 (1993).

    Article  CAS  Google Scholar 

  17. O'Brien, R.D., Rotenoids. Insecticides. Action and Metabolism 159–163 (Academic Press, New York, 1967).

  18. Fukami, H. & Nakajima, M. Rotenone and rotenoids. Naturally Occurring Insecticides 71–97 (Dekker, New York, 1971).

  19. Burgos, J. & Redfearn, E.R. The inhibition of mitochondrial reduced nicotinamide-adenine dinucleotide oxidation by rotenoids. Biochim. biophys. Acta 110, 475–483 (1965).

    Article  Google Scholar 

  20. Marshall, L.E. & Himes, R.H. Rotenone inhibition of tubulin self-assembly. Biochim. biophys. Acta 543, 590–594 (1978).

    Article  CAS  Google Scholar 

  21. Anzeveno, P.B., Rotenoid Interconversion. Synthesis of deguelin from rotenone. J. org. Chem. 44, 2578–2580 (1979).

    Article  CAS  Google Scholar 

  22. O'Brien, T.G. The induction of ornithine decarboxylase as an early, possibly obligatory event in mouse skin carcinogenesis. Cancer Res. 36, 2644–2653 (1976).

    CAS  PubMed  Google Scholar 

  23. Lu, Y.-P., Chang, R.L., Huang, M.-T. & Conney, A.H. Inhibitory effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced increase in ornithine decarboxylase mRNA in mouse epidermis. Carcinogenesis 14, 293–297 (1993).

    Article  CAS  Google Scholar 

  24. Wagner, A.J., Meyers, C., Laimins, L.A. & Hay, N. c-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ. 4, 879–883 (1993).

    CAS  PubMed  Google Scholar 

  25. Bello-Fernandez, C. & Cleveland, J.L. C-myc transactivates the ornithine decarboxylase gene. Curr. Topics Microbiol. Immunol. 182, 445–452 (1992).

    CAS  Google Scholar 

  26. Kakar, S.S. & Roy, D. Curcumin inhibits TPA-induced expression of c-fos, c-jun and c-myc proto-oncogenes messenger RNAs in mouse skin. Cancer Lett. 87, 85–89 (1994).

    Article  CAS  Google Scholar 

  27. Lichti, U. & Gottesman, M.M. Genetic evidence that a phorbol ester tumor promoter stimulates ornithine decarboxylase activity by a pathway that is independent of cyclic AMP-dependent protein kinases in CHO cells. J. Cell Physiol. 113, 433–439 (1982).

    Article  CAS  Google Scholar 

  28. Lowry, O.H., Rosebrough, N.J., Farr, A.L. & Randall, R.J. Protein measurement with the folin phenol reagent. J. biol. Chem. 193, 265–275 (1951).

    CAS  PubMed  Google Scholar 

  29. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  30. Kroczek, R.A. & Siebert, E. Optimization of northern analysis by vacuum-blotting, RNA-transfer visualization, and ultraviolet fixation. Anal. Biochem., 184, 90–95 (1990).

    Article  CAS  Google Scholar 

  31. De Vries, D.J., Herald, C.L., Pettit, G.R. & Blumberg, P.M. Demonstration of sub-nanomolar affinity of bryostatin 1 for the phorbol ester receptor in rat brain. Biochem. Pharmacol. 37, 4069–4073 (1988).

    Article  CAS  Google Scholar 

  32. Da Silva, C., Fan, X., Martelly, I. & Castagna, M. Phorbol ester mediated phospholipid-free activation of rat brain protein kinase C. Cancer Res. 50, 2081–2087 (1990).

    CAS  PubMed  Google Scholar 

  33. Chen, I.-S. et al. Chemical and bioactive constituents from Zanthoxylum simulans . J. Nat. Prod. 54, 1206–1211 (1994).

    Article  Google Scholar 

  34. McCormick, D.L. & Moon, R.C. Antipromotional activity of dietary N-(4-hydroxyphenyl) retinamide in two-stage skin tumourigenesis in CD-1 and Sencar mice. Cancer Lett. 31, 133–138 (1986).

    Article  CAS  Google Scholar 

  35. Mehta, R.G., Steele, V., Kelloff, G.J. & Moon, R.C. Influence of thiols and inhibitors of prostaglandin biosynthesis on the carcinogen-induced development of mammary lesions in vitro . Anticancer Res. 11, 587–592 (1991).

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Woongchon Mar

    Present address: Natural Products Research Institute, Seoul National University, Seoul, 110-460, Korea

Authors and Affiliations

  1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, 60612, USA

    Clarissa Gerhäuser, Woongchon Mar, Sang Kook Lee, Nanjoo Suh, Yingde Luo, Lumonadio Luyengi, Harry H.S. Fong, A. Douglas KingHorn, Rajendra G. Mehta & John M. Pezzuto

  2. Department of Chemistry, College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois, 60612, USA

    Jerome Kosmeder & Robert M. Moriarty

  3. Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, USA

    Rajendra G. Mehta, Andreas Constantinou, Richard C. Moon & John M. Pezzuto

Authors
  1. Clarissa Gerhäuser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Woongchon Mar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sang Kook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nanjoo Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingde Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jerome Kosmeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lumonadio Luyengi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Harry H.S. Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Douglas KingHorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert M. Moriarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rajendra G. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andreas Constantinou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Richard C. Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John M. Pezzuto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gerhäuser, C., Mar, W., Lee, S. et al. Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase. Nat Med 1, 260–266 (1995). https://doi.org/10.1038/nm0395-260

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0395-260

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing