Skip to main content

Effects of Protease Inhibitors and Vitamin E in the Prevention of Cancer

  • Chapter

Part of the book series: Experimental Biology and Medicine ((EBAM,volume 23))

Summary

Protease inhibitors and Vitamin E have been the most effective of the potential human cancer chemopreventive agents we have studied in the ability to suppress radiation-induced malignant transformation i in vitro. Although neither of these agents affect malignant cells, they appear to be working by different mechanisms to suppress the conversion of a cell to the malignant state, as their in vitro effects are markedly different. The effects of Vitamin E are reversible; if the compound is removed from cultures destined to produce transformed foci, transformed cells arise. The effects of protease inhibitors are irreversible in that these agents need to be present in cultures for only short periods of time to reverse the carcinogenic process (1). Protease inhibitors have their suppressive effect on carcinogenesis when present while cells are actively proliferating (1); vitamin E is effective when cells are in the confluent, stationary phase of growth (2). Relatively large concentrations of vitamin E (at nearly toxic levels) are necessary to inhibit transformation in vitro, while very low concentrations of protease inhibitor (nanomolar-picomolar ranges) are capable of suppressing the transformation process (1,2).

Protease inhibitors have proven to be so effective in our studies on the prevention of radiation transformation in vitro that we have now performed many other studies to determine the effects of these agents in animal model carcinogenesis systems. Studies with the soybean-derived Bowman-Birk inhibitor have shown that this protease inhibitor is capable of suppressing dimethylhydrazine-induced colon (3,4) and liver (4) carcinogenesis in mice, 7, 12 dimethylbenz(a)anthracene-induced oral carcinogenesis in hamsters (5) and 3-methylcholanthrene-induced lung tumorigenesis in mice (Witschi and Kennedy, unpublished data). Studies on the mechanism of the protease inhibitor suppression of carcinogenesis have suggested that these agents may act by suppressing oncogene expression or specific proteases involved in the conversion of a cell to the malignant state.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Kennedy, A.R. The conditions for the modification of radiation transformation in vitro by a tumor promoter and protease inhibitors. Carcinogenesis 6: 1441–1446, 1985.

    Article  CAS  Google Scholar 

  2. Radner, B.S. and Kennedy, A.R. Suppression of x-ray induced transformation by Vitamin E in mouse C3H/10T1/2 cells. Cancer Letters 31: 25–32, 1986.

    Google Scholar 

  3. Weed, H., McGandy, R.B. and Kennedy, A.R. Protection against dimethylhydrazine induced adenomatous tumors of the mouse colon by the dietary addition of an extract of soybeans containing the Bowman-Birk protease inhibitor. Carcinogenesis 6: 1239–1241, 1985.

    Article  CAS  Google Scholar 

  4. St. Clair, W., Billings, P., Carew, J., Keller-McGandy, C., Newberne, P. and Kennedy, A.R. Suppression of DMH-induced carcinogenesis in mice by dietary addition of the Bowman-Birk protease inhibitor. (submitted)

    Google Scholar 

  5. Messadi, P.V., Billings, P., Shklar, G. and Kennedy, A.R. Inhibition of oral carcinogenesis by a protease inhibitor. J. Natl. Cancer Inst. 76: 447–452, 1986.

    CAS  Google Scholar 

  6. Kennedy, A.R. Promotion and other interactions between agents in the induction of transformation in vitro in fibroblasts. In: Mechanisms of Tumor Promotion, Vol. III, “Tumor Promotion and Carcinogenesis In Vitro” edited by T.J. Slaga, CRC Press, Inc., Chapter 2, pp. 13–55, 1984.

    Google Scholar 

  7. Kennedy, A.R. and Little, J.B. Protease inhibitors suppress radiation induced malignant transformation in vitro. Nature 276: 825–826, 1978.

    Article  CAS  Google Scholar 

  8. Kennedy, A.R. and Weichselbaum, R.R. Effects of 17-B- estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors. Carcinogenesis 2: 67–69. 1981.

    Article  CAS  Google Scholar 

  9. Kennedy, A.R. and Little, J.B. Effects of protease inhibitors on radiation transformation in vitro. Cancer Res. 41: 2103–2108, 1981.

    CAS  Google Scholar 

  10. Kennedy, A.R. Antipain, but not cycloheximide, suppresses radiation transformation when present for only one day at five days post-irradiation. Carcinogenesis 1: 1093–1095, 1982.

    Article  Google Scholar 

  11. Yavelow, J., Finlay, T.H., Kennedy, A.R. and Troll, W. Bowman-Birk soybean protease inhibitor as an anticarcinogen. Cancer Res. 43: 2454–2459, 1983.

    CAS  Google Scholar 

  12. Kennedy, A.R. Prevention of Radiation-Induced Transformation In Vitro, In: Vitamins. Nutrition and Cancer (ed. K.N. Prasad), S. Karger, A.G. Basel, pp. 166–179, 1984.

    Google Scholar 

  13. Yavelow, J., Collins, M., Birk, Y., Troll, W. and Kennedy, A.R. Nanomolar concentrations of Bowman-Birk soybean protease inhibitor suppress X-ray induced transformation in vitro. Proc. Natl. Acad. Sci. USA 82: 5395–5399, 1985.

    Article  CAS  Google Scholar 

  14. Baturay, N.Z. and Kennedy, A.R. Pyrene acts as a cocarcinogen with the carcinogens, benzo(a)pyrene, Bpropiolactone and radiation in the induction of malignant transformation of cultured mouse fibroblasts; soybean extract containing the Bowman-Birk inhibitor acts as an anticarcinogen. Cell Biol Toxicol. 2: 21–32, 1986.

    Article  CAS  Google Scholar 

  15. Kennedy, A.R. Implications for mechanisms of tumor promotion and its inhibition by various agents from studies of in vitro transformation. In: Tumor Promoters, Biological Approaches for Mechanistic Studies and Assay Systems. (Editors: Langenbach, R., Barrett, J.C. and Elmore, E.), Raven Press, New York, pp. 201–212, 1988.

    Google Scholar 

  16. Billings, P.C., St. Clair, W., Ryan, C.A. and Kennedy, A.R. Inhibition of radiation-induced transformation of C3H/10T1/2 cells by chymotrypsin inhibitor 1 from potatoes. Carcinogenesis 8: 809–812, 1987.

    Article  CAS  Google Scholar 

  17. Kennedy, A.R. and Billings, P.C. Anticarcinogenic actions of protease inhibitors. Proceedings of the 2nd International Conference on “Anticarcinogenesis and Radiation Protection,” Cerutti, P.A., Nygaard, O.F.and Simic, M.G., editors), Plenum Press, New York, pp. 285–295, 1987.

    Google Scholar 

  18. Kakunaga, T. A. Quantitative system for assay of malignant transformation by chemical carcinogens using a clone derived from BALB/3T3. Int. J. Cancer 12: 463–473, 1973.

    CAS  Google Scholar 

  19. Little, J.B. Quantitative studies of radiation transformation with the A31–11 mouse BALB/3T3 cell line. Cancer Res. 39: 1474–1480, 1979.

    Google Scholar 

  20. Cortese, E., Saffiotti, U., Donovan, P.J., Rice, J.M. and Kakunaga, T. Dose-response studies on neoplastic transformation of Balb/3T3 clone A31–11 cells by Aflatoxin B, Benzidine, Benzo(a)pyrene, 3-Methylcholanthrene and N-methyl-N1 -ni troN-nitroso-guanidine. Teratogenesis, Carcinogenesis, Mutagenesis 2: 101–110, 1983.

    Article  Google Scholar 

  21. Baturay, N.Z., Targovnik, H.S., Reynolds, R.J. and Kennedy, A.R. Induction of in vitro transformation by near UV light and its interaction with Beta-propiolactone. Carcinogenesis 5: 465–468, 1985.

    Article  Google Scholar 

  22. Symons, M.C.R. and Kennedy, A.R. “ Water structure” versus “radical scavenger” theories as explanations for the suppressive effects of DMSO and related compounds on radiation-induced transformation in vitro. Carcinogenesis 8: 683–688, 1987.

    Article  Google Scholar 

  23. Vanderhoek, J.Y., Makheja, A.M., and Bailey, J.M. Inhibition of fatty acid oxygenases by onion and garlic oils. Biochemical Pharmacology 22: 3169–3173, 1980.

    Article  Google Scholar 

  24. De Luca, H.F. and Schnoes, H.K. Metabolism and mechanism of action of vitamin D. Ann. Rev. Biochem. 45: 631–642, 1976.

    Article  Google Scholar 

  25. Kuroki, T., Sasaki, K., Kazuhiro, C., Abe, E. and Suda, T. la,25Dihydroxyvitamin D3 markedly enhances chemically-induced transformation in Balb 3T3 cells. Gann 74: 611–614, 1983.

    CAS  Google Scholar 

  26. Eisman, J.A., Barkla, D.H., and Tutton, P.J.M. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25dihydroxyvitamin D3. Cancer Research 47: 21–25, 1987.

    CAS  Google Scholar 

  27. Frampton, R.J., Omond, S.A., and Eisman, J.A. Inhibition of human cancer growth by 1,25-dihydroxyvitamin D3 metabolites. Cancer Research 43: 4443–4447, 1983.

    CAS  Google Scholar 

  28. Colston, D, Colston, M.J., and Feldman, M. 1,25Dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108: 1083–1086, 1981.

    Article  CAS  Google Scholar 

  29. Borek, C., Ong, A., Mason, H., Donahue, L., and Biaglow, J. Selenium and vitamin E inhibit radiogenic and chemically induced transformation in vitro via different mechanisms. Proc. Natl. Acad. Sci. 83: 1490–1494, 1986.

    Article  CAS  Google Scholar 

  30. Grobstein, C. (Chairman of Committee). Diet, Nutrition and Cancer.Committee On Diet, Nutrition and Cancer, National Acadamy of Sciences, National Acadamy Press, Washington, D.C.,1982.

    Google Scholar 

  31. Chang, J.D. Billings, P. and Kennedy, A.R. C-myc expression is reduced in antipain-treated proliferating CH10T1/2 cells. Biochem.Biophys. Res Comm. 133: 830–835, 1985.

    CAS  Google Scholar 

  32. Billings, P.C., Carew, J.A., Keller-McGandy, C.E., Goldberg, A., and Kennedy, A.R. A serine protease activity in C3H10T1/2 cells that is inhibited by anticarcinogenic protease inhibitors. Proc. Natl.Acad. Sci. 84: 4801–4805, 1987.

    Article  CAS  Google Scholar 

  33. Chang, J.D. and Kennedy, A.R. Cell cycle progression of C3H10T1/2 cells and 3T3 cells in the absense of a transient increase in c-myc RNA levels. Carcinogenesis 9: 17–20, 1988.

    Article  CAS  Google Scholar 

  34. Billings, P.C., St. Clair, W., Owen, A. J. and Kennedy, A.R. Potential intracellular target proteins of the anticarcinogenic Bowman-Birk protease inhibitor identified by affinity chromatography. Cancer Res. 48: 1798–1802, 1988.

    CAS  Google Scholar 

  35. Billings, P.C., St. Clair, W., Owen, A. J. and Kennedy, A.R. Potential intracellular target proteins of the anticarcinogenic Bowman-Birk protease inhibitor identified by affinity chromatography. Cancer Res. 48: 1798–1802, 1988.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1990 The Humana Press Inc.

About this chapter

Cite this chapter

Kennedy, A.R. (1990). Effects of Protease Inhibitors and Vitamin E in the Prevention of Cancer. In: Prasad, K.N., Meyskens, F.L. (eds) Nutrients and Cancer Prevention. Experimental Biology and Medicine, vol 23. Humana Press. https://doi.org/10.1007/978-1-4612-4516-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4612-4516-2_6

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-4612-8856-5

  • Online ISBN: 978-1-4612-4516-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics