Antioxidants as Antitumor Promoters

  • Walter J. Kozumbo
  • Peter A. Cerutti
Part of the Basic Life Sciences book series (BLSC, volume 39)


Phorbol 12-myristate 13-acetate (PMA) is a potent mouse skin tumor promoter which has been researched most intensively over the years in an attempt to understand the biochemical mechanisms involved in tumor promotion, PMA stimulates a multitude of cellular and biochemical reactions (82), Three of these, induction of ornithine decarboxylase (ODC) activity, hyperplasia and inflammation, correlate well with tumor promotion in mouse skin, and each is considered to be a necessary but insufficient event in this process (22, 27, 51, 58, 64, 70, 83) The release of metabolites of arachidonic acid (AA) is also thought to be important in view of the inhibitory effects of nonsteroidal anti-inflammatory drugs on PMA-induced ODC activity and tumor promotion (19, 48).


Arachidonic Acid Benzoyl Peroxide Tumor Promotion Mouse Skin Ornithine Decarboxylase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ager, A., and J.L. Jordon (1984) Differential effects of hydrogen peroxide on indices of endothelial cell function. J. Exp. Med. 159:592–603.CrossRefGoogle Scholar
  2. 2.
    Althaus, F., S.D. Lawrence, Y.Z. He, G.L. Sattler, Y. Tsukda, and H.C. Pitot (1982) Effects of altered (ADP-ribose) metabolism on expression of fetal functions by adult l3miphocytes. Nature 300:366–368.CrossRefGoogle Scholar
  3. 3.
    Birnboim, H.C. (1983) Importance of DNA strand-break damage in tumor promotion. In Radioprotectors and Anticarcinogens, O.F. Nygaard and M.G. Simic, eds. Academic Press, New York, pp. 539–556.Google Scholar
  4. 4.
    Birnboim, H.C. (1982) DNA strand breakage in human leukocytes exposed to a tumor promoter, phorbol myristate acetate. Science 215:1247–1249.CrossRefGoogle Scholar
  5. 5.
    Borek, C., W.F. Morgan, A. Ong, and J.E. Cleaver (1984) Inhibition of malignant transformation in vitro by inhibitors of poly (ADP-ribose) synthesis. Proc. Natl. Acad. Sci. USA 81:243–247.CrossRefGoogle Scholar
  6. 6.
    Borek, C., and W. Troll (1983) Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. Proc. Natl. Acad. Sci., USA 80:1304–1307.CrossRefGoogle Scholar
  7. 7.
    Bradley, M., and L. Erickson (1981) Comparison of the effects of hydrogen peroxide and X-irradiation on toxicity, mutation and DNA damage repair in mammalian cells. Biochim. Biophys. Acta 654:135–141.Google Scholar
  8. 8.
    Bull, A.W., N.D. Nigro, W.A. Golembieski, J.D. Crissman, and L.J. Marnett (1984) In vivo stimulation of DNA synthesis and induction of ornithine decarboxylase in rat colon by fatty acid hydroperoxides, autoxidation products of unsaturated fatty acids. Cancer Res. 44:4924–4928.Google Scholar
  9. 9.
    Cerutti, P.A. (1985) Prooxidant states and tumor promotion. Science 227:375–381.CrossRefGoogle Scholar
  10. 10.
    Cook, H.W., and W.E.M. Lands (1976) Mechanism for suppression of cellular biosynthesis of prostaglandins. Nature 260:630–632.CrossRefGoogle Scholar
  11. 11.
    Dutton, D.R., and G.T. Bowden (1985) Indirect induction of a clastogenic effect in epidermal cells by a tumor promoter. Carcinogenesis 6(9):1279–1284.CrossRefGoogle Scholar
  12. 12.
    Durkacz, B.W., O. Omidiji, D.A. Gray, and S. Shall (1980) (ADP-ribose)n participates in DNA excision repair. Nature 283:593–596.CrossRefGoogle Scholar
  13. 13.
    Eling, T., B. Tainer, A. Ally, and R. Warnock (1982) Separation of arachidonic acid metabolites by high pressure liquid chromatography. In Methods of Enzymology, Vol. 86, W.E.M. Lands and W.L. Smith, eds. Academic Press, New York, pp. 511–517.Google Scholar
  14. 14.
    Emerit, I., and P.A. Cerutti (1982) Tumor promoter phorbol 12-myristate 13-acetate induces a clastogenic factor in human lymphocytes. Proc. Natl. Acad. Sci., USA 79:7509–7513.CrossRefGoogle Scholar
  15. 15.
    Emerit I., and P. Cerutti (1983) Clastogenic action of tumor promoter phorbol-12-myristate-13-acetate in mixed human leukocyte cultures. Carcinogenesis 4:1313–1316.CrossRefGoogle Scholar
  16. 16.
    Emerit, I., S.H. Khan, and P.A. Cerutti (1985) Treatment of lymphocyte cultures with a hypoxanthine-xanthine oxidase system induces the formation of transferable clastogenic material. J Free Radicals in Biol and Med. l(l):51–58.CrossRefGoogle Scholar
  17. 17.
    Emerit, I., and P. Cerutti (unpublished observations).Google Scholar
  18. 18.
    Farzaneh, F., R. Zalin, D. Brell, and S. Shall (1982) DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation. Nature 300:362–366.CrossRefGoogle Scholar
  19. 19.
    Fischer, S.M. (1985) Arachidonic acid metabolism and tumor promotion. In Arachidonic Acid Metabolism and Tumor Promotion, S.M. Fischer and T.J. Slaga, eds. Martinus Nijhoff Publishing, pp. 22–47.CrossRefGoogle Scholar
  20. 20.
    Fischer, S.M., and L.M. Adams (1985) Suppression of tumor promoter-induced chemiluminescence in mouse epidermal cells by several inhibitors of arachidonic acid metabolism. Cancer Res. 45:3130–3136.Google Scholar
  21. 21.
    Friedman, J., and P. Cerutti (1983) The induction of ornithine decarboxylase by phorbol 12-myristate 13-acetate or by serum is inhibited by antioxidants. Carcinogenesis 4:1425–1427.CrossRefGoogle Scholar
  22. 22.
    Furstenberger, G., and F. Marks (1985) Prostaglandins, epidermal hyperplasia and skin tumor promotion. In Arachidonic Acid Metabolism and Tumor Promotion, S.M. Fischer and T.J. Slaga, eds. Martinus Nijhoff Publishing, pp. 50–72.Google Scholar
  23. 23.
    Goldstein, B.D., G. Witz, M. Amoruso, D.S. Stone, and W. Troll (1981) Stimulation of human polymorphonuclear leukocyte superoxide anion radical production by tumor promoters. Cancer Lett. 11:257–262.CrossRefGoogle Scholar
  24. 24.
    Goldstein, B.D., G. Witz, M. Amoruso, and W. Troll (1979) Protease inhibitors antagonize the activation of pol3miorphonuclear leukocyte oxygen consumption. Biochem. Biophys. Res. Commun. 88:854–860.CrossRefGoogle Scholar
  25. 25.
    Goldstein, B., G. Witz, J. Zimmerman, and C. Gee (1983) Free radicals and reactive oxygen species in tumor promotion. In Oxy Radicals and their Scavenger Systems, Vol. II, Cellular and Medical Aspects, R.A. Greenwald and G. Cohen, eds. Elsevier, New York, pp. 321–325.Google Scholar
  26. 26.
    Hartley, J.A., N.W. Gibson, L.A. Zwelling, and S.H. Yuspa (1985) Strand breaks in mouse epidermal DNA are associated with phorbol ester induced differentiation. Proc. Am. Assoc. Cancer Res. 26:42.Google Scholar
  27. 27.
    Hecker, E. (1978) Structure-activity relationships in diterpene esters irritant and cocarcinogenic to mouse skin. In Carcinogenesis—A Comprehensive Survey, Vol. II, Mechanisms of Tumor Promotion and Cocarcinogenesis, T.J. Slaga, A. Sivak, and R.K. Boutwell, eds. Raven Press, New York, pp. 11–48.Google Scholar
  28. 28.
    Hemler, M.E., H.W. Cook, and W.E.M. Lands (1979) Prostaglandin biosynthesis can be triggered by lipid peroxides. Arch. Biochem. Biophys. 193(2):340–345.CrossRefGoogle Scholar
  29. 29.
    Hemler, M.E., and W.E.M. Lands (1980) Evidence for a peroxide-initiated free-radical mechanism of prostaglandin biosynthesis. J. Biol. Chem. 255(13):6253–6261.Google Scholar
  30. 30.
    Holland, J.M., E.H. Perkinds, and L.C. Gipson (1977) Resistance of germ free athymic nude mice to two-stage epidermal carcinogenesis. Proc. Am. Assoc. Cancer Res. 18:10.Google Scholar
  31. 31.
    Iwashita, S., and C. Fox (1984) Epidermal growth factor and potent phorbol tumor promoters induce epidermal growth factor receptor phosphorylation in a similar but distinctively different manner in human epidermoid carcinoma A431 cells. J. Biol. Chem. 259:2559–2567.Google Scholar
  32. 32.
    Jacobson, E.L., K.M. Antol, H. Juarez-Salinas, and M.K. Jacobson (1983) Poly (ADP-ribose) metabolism in ultraviolet-irradiated human fibroblasts. J. Biol. Chem. 258:103–107.Google Scholar
  33. 33.
    Johnstone, A.P., and G.T. Williams (1982) Role of DNA breaks and ADP-ribose transferase activity in eukaryotic differentiation demonstrated in human lymphocytes. Nature 300:368–370.CrossRefGoogle Scholar
  34. 34.
    Kensler, T.W. (personal communication).Google Scholar
  35. 35.
    Kensler, T.W., and M.A. Trush (1984) Role of oxygen radicals in tumor promotion. Environ. Mutag. 6:593–616.CrossRefGoogle Scholar
  36. 36.
    Kensler, T.W., D.M. Bush, and W.J. Kozumbo (1983) Inhibition of tumor promotion by a biomimetic superoxide dismutase. Science 221:75–77.CrossRefGoogle Scholar
  37. 37.
    Kensler, T.W., and M.A. Trush (1983) Inhibition of oxygen radical metabolism in phorbol ester-activated polymorphonuclear leukocytes by antitumor-promoting copper complex with superoxide dismutase-mimetic activity. Biochem. Pharmacol. 32(22):3485–3487.CrossRefGoogle Scholar
  38. 38.
    Kidwell, W.R., and M.G. Mage (1976) Changes in poly (adenosine diphosphate ribose) and poly (adenosine diphosphate) polymerase in synchronous Hela cells. Eur. J. Biochem. 15:1213–1217.Google Scholar
  39. 39.
    Klein-Szanto, A.J.P. and T.J. Slaga (1982) Effects of peroxides on rodent skin: Epidermal hyperplasia and tumor promotion. Invest. Derma. 79:30–34.CrossRefGoogle Scholar
  40. 40.
    Kozumbo, W.J., D. Muhlematter, A. Jorg, I. Emerit, and P.A. Cerutti (1985) Release of membrane lipids from human monocytes stimulated by the tumor promoter phorbol-12-myrlstate--13-acetate (submitted for publ.).Google Scholar
  41. 41.
    Kozumbo, W.J., J.L. Seed, and T.W. Kensler (1983) Inhibition by 2(3)-tert-butyl-4-hydroxyanisole and other antioxidants of epidermal ornithine decarboxylase activity induced by 12-0-tetradecanoylphorbol-13-acetate. Cancer Res, 43:2555–2559.Google Scholar
  42. 42.
    Kozumbo, W.J., M.A. Trush, and T.W. Kensler (1985) Are free radicals involved in tumor promotion? Chem. Biol. Interact. 40:199–209.CrossRefGoogle Scholar
  43. 43.
    Kun, E., E. Kirsten, G.E. Milo, P. Kurian, and H.L. Kumari (1983) Cell cycle-dependent intervention by benzamide of carcinogen-induced neoplastic transformation and in vitro poly ADP-ribosylation of nuclear proteins in human fibroblasts. Proc. Natl. Acad. Sci., USA 80:7219–7223.CrossRefGoogle Scholar
  44. 44.
    Lewis, J.G., and D.O. Adams (1985) Induction of 5,6-ring-saturated thinnine bases in NIH-3T3 cells by phorbol ester-stimulated macrophages Role of reactive oxygen intermediates. Cancer Res. 45:1270–1275.Google Scholar
  45. 45.
    Lupulescu, A. (1984) Tumorigenic potential of endoperoxide analogs. Experientia 40:209–211.CrossRefGoogle Scholar
  46. 46.
    Marnett, L.J. (personal communication).Google Scholar
  47. 47.
    Michelson, A.M., K. Puget, P. Durosay, and A. Rosselet (1980) Penetration of erythrocytes by superoxide dismutase. In Biological and Clinical Aspects of Superoxide and Superoxide Dismutase, W.H. Bannister and J.V. Bannister, eds. Elsevier, New York, pp. 348–366.Google Scholar
  48. 48.
    Nakadate, T., S. Yammamoto, M. Ishii, and R. Kato (1982) Inhibition of 12-0-tetradecarioylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by lipooxygenase inhibitors: Possible role of product(s) of lipoxygenase pathway. Carcinogenesis 3:1411–1414.CrossRefGoogle Scholar
  49. 49.
    Nagasawa, H., and J.B. Little (1981) Factors influencing the induction of sister chromatid exchanges in mammalian cells by 12-0-tetradecanoyl-phorbol-13-acetate. Carcinogenesis 2:601–607.CrossRefGoogle Scholar
  50. 50.
    Nakamura, Y., N.H. Colburn, and T.D. Gindhart (1985) Role of reactive oxygen in tumor promotion: Implication of superoxide anion in promotion of neoplastic transformation in JB-6 cells by TPA. Carcinogenesis 6:229–235.CrossRefGoogle Scholar
  51. 51.
    O’Brien, T.G. (1976) The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis. Cancer Res. 36:2644–2653.Google Scholar
  52. 52.
    Ochi, T., and P.A. Cerutti (unpublished observations).Google Scholar
  53. 53.
    Patskan, G., and C. St. Baxter (1985) Specific stimulation by phorbol esters of the phosphorylation of histones H2B and H4 in murine lymphocytes. Cancer Res. 45:667–672.Google Scholar
  54. 54.
    Pederson, T.C., and S.D. Aust (1973) The role of superoxide and singlet oxygen in lipid peroxidation promoted by xanthine oxidase, Biochem. Biophys. Res. Commun. 52:1071–1078.CrossRefGoogle Scholar
  55. 55.
    Perchellet, J.P., M.D. Owen, T.D. Posey, D.K. Orten, and B.A. Schneider (1982) Inhibitory effects of glutathione level-raising agents and D-tocopherol on ornithine decarboxylase induction and mouse skin tumor promotion by 12-0-tetradecanoylphorbol-13-acetate, Carcinogenesis 6: 567–573.CrossRefGoogle Scholar
  56. 56.
    Rossman, T.G., and W. Troll (1980) Protease inhibitors in carcinogenesis, possible sites of action. In Modifiers of Chemical Carcinogenesis, Vol. 5, T.J. Slaga, ed. Raven Press, New York, pp. 127–143.Google Scholar
  57. 57.
    Scher, W., and C. Friend (1978) Breakage of DNA and alterations in folded genomes by inducers of differentiation in Friend erythroleukemia cells. Cancer Res. 38:841–849.Google Scholar
  58. 58.
    Schmidt, R., W. Adolf, A. Marston, H. Roser, B. Sorg, H. Fujiki, T. Sugimura, R.E. Moore, and E. Hecker (1983) Inhibition of specific binding of 3H phorbol-12,13~dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin. Carcinogenesis 4:77–81.CrossRefGoogle Scholar
  59. 59.
    Shamberger, R.J. (1972) Increase of peroxidation in carcinogenesis. J. Natl. Cancer Inst. 48(5):1491–1497.Google Scholar
  60. 60.
    Singh, N., G. Poirier, and P. Cerutti (1985) Tumor promoter phorbol-12-myristate-13-acetate induces poly (ADP)-ribosylation in fibroblasts. EMBO J. 4:1491–1494.Google Scholar
  61. 61.
    Singh, N., G. Poirier, and P. Cerutti (1985) Tumor promoter phorbol-12-myristate-13-acetate induces poly ADP-ribosylation in human monocytes. Biochem. Biophys. Res. Commun. 126:1208–1214.CrossRefGoogle Scholar
  62. 62.
    Singh, N., and P.A. Cerutti (1985) Poly ADP-ribosylation of histones in tumor promoter phorbol-12-myristate-13-acetate treated mouse embryo fibroblasts C3H10T1/2 (submitted for publ.).Google Scholar
  63. 63.
    Singh, N., Y. Leduc, G. Poirier, and P. Cerutti (1985) Non-histone chromosomal protein acceptors for poly ADP-ribose in phorbol-12-myristate-13-acetate-treated mouse embryo fibroblasts C3H10T1/2. Carcinogenesis (in press).Google Scholar
  64. 64.
    Slaga, T.J., S.M. Fischer, A. Viaje, D.L. Berry, W.M. Bracken, S. Le Clerc, and D.R. Miller (1978) Inhibition of tumor promotion by antiinflammatory agents: An approach to the biochemical mechanism of promotion. In Carcinogenesis, Vol. 2, Mechanisms of Tumor Promotion and Cocarcinogenesis, T.J. Slaga, A. Sivak, and R.K. Boutwell, eds. Raven Press, New York, pp. 173–195.Google Scholar
  65. 65.
    Slaga, T.J., V. Solanki, and M. Logani (1983) Studies on the mechanisms of action of antitumor promoting agents: Suggestive evidence for the involvement of free radicals in promotion. In Radioprotectors and Anticarcinogens, O.F. Nygaard and M.G. Simic, eds. Academic Press, New York, pp. 471–485.Google Scholar
  66. 66.
    Slaga, T.J., A.J.P. Klein-Szanto, L.L. Triplett, L.P. Yotti, and J.E. Trosko (1981) Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound. Science 213:1023–1025.CrossRefGoogle Scholar
  67. 67.
    Smith, M.T., H. Thor, S.A. Jewell, G. Bellomo, M.S. Sandy, and S. Orrenius (1984) Free radical-induced changes In the surface morphology of isolated hepatocytes. In Free Radicals in Molecular Biology, Aging and Disease, D. Armstrong, R.S. Sohal, R.G. Cutler, and T.F. Slater, eds. Raven Press, New York, pp. 103–118.Google Scholar
  68. 68.
    Solanki, V., R.S. Rana, and T.J. Slaga (1981) Diminution of mouse epidermal superoxide dismutase and catalase activities by tumor promoters. Carcinogenesis 2:1141–1146.CrossRefGoogle Scholar
  69. 69.
    Srinivas, L., and N.H. Colburn (1984) Preferential oxidation of cell surface sialic acid by periodate leads to promotion of transformation in JB-6 cells. Carcinogenesis 5:515–519.CrossRefGoogle Scholar
  70. 70.
    Suganuma, M., H. Fujiki, T. Tomoko, C. Cheuk, R.E. Moore, and T. Sugimura (1984) Estimation of tumor-promoting activity and structure-function relationships of aplysiatoxins. Carcinogenesis 5:315–318.CrossRefGoogle Scholar
  71. 71.
    Takayma, S., M. White, V. Lauris, and C. Kuhn (1984) Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells. Proc. Natl. Acad. Sci., USA 81:7797–7801.CrossRefGoogle Scholar
  72. 72.
    Tanigawa, Y., A. Kitamura, M. Kawamura, and M. Shimoyama (1978) Effect of poly (ADP-ribose) formation on DNA synthesis in chick-embryo-liver nuclei. Eur. J. Biochem. 92:261–269.CrossRefGoogle Scholar
  73. 73.
    Taylor, L., M.J. Menconi, and P. Polgar (1983) The participation of hydroperoxides and oxygen radicals in the control of prostaglandin synthesis. J. Biol. Chem. 258(11):6855–6857.Google Scholar
  74. 74.
    Terada, M., U. Nudel, E. Fibach, R.A. Rifkind, and P.A. Marks (1978) Changes in DNA associated with induction of erythroid differentiationby dimethyl sulfoxide in murine erythroleukemia cells. Cancer Res. 38:835–840.Google Scholar
  75. 75.
    Thomas, M.J., S. Mehl, and W.A. Pryor (1978) The role of the superoxide anion in the xanthine oxidase-induced autoxidation of linoleic acid. Biochem. Biophys. Res. Commun. 83:927–932.CrossRefGoogle Scholar
  76. 76.
    Verma, A.K., C.L. Astendel, and R.K. Boutwell (1980) Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-0-tetradecanoylphorbol-13-acetate. Cancer Res. 40:308–315.Google Scholar
  77. 77.
    Verma, A.K., T.J. Slaga, P.W. Wertz, G.C. Mueller, and R.K. Boutwell (1980) Inhibition of skin tumor promotion by retinoic acid and its metabolites 5,6-epoxyretinoic acid. Cancer Res. 40:2367–2371.Google Scholar
  78. 78.
    Weitberg, A.B., S.A. Weitzman, E.P. Clark, and T.P. Stossel (1985) Effects of antioxidants on oxidant-induced sister chromatid exchange formation. J. Clin. Invest. 75:1835–1841.CrossRefGoogle Scholar
  79. 79.
    Weitberg, A.B., S.A. Weitzman, M. Destrempes, S.A. Latt, and T.P. Stossel (1983) Stimulated human phagocytes produce cytogenetic changes in cultured mammalian cells. New Eng. J. Med. 308:26–30.CrossRefGoogle Scholar
  80. 80.
    Weiss, S.J., A.F. Lobuglio, and H.B. Kessler (1980) Oxidative mechanisms of monocyte-mediated cytotoxicity. Proc. Natl. Acad. Sci., USA 77:584–587.CrossRefGoogle Scholar
  81. 81.
    Weitzman, S.A., and T.P. Stossel (1982) Effects of oxygen radical scavengers and antioxidants on phagocyte-induced mutagenesis. J. Imm. 128:2770–2772.Google Scholar
  82. 82.
    Yuspa, S.H. (1984) Mechanisms of tumor promotion. In Tumor Promotion and Carcinogenesis In Vitro (“Mechanisms of Tumor Promotion,” Vol. 3), T.J. Slaga, ed. CRC Press, Boca Raton, Florida, pp. 1–11.Google Scholar
  83. 83.
    Yuspa, S.H., U. Lichti, T. Ben, E. Patterson, and H. Hennings (1976) Phorbol-esters stimulate DNA synthesis and ornithine decarboxylase activity in mouse epidermal cell cultures. Nature 262:402–404.CrossRefGoogle Scholar
  84. 84.
    Yuspa, S.H., T. Ben, H. Hennings, and U. Lichti (1982) Divergent responses in epidermal basal cells exposed to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. Cancer Res. 42:2344–2349.Google Scholar
  85. 85.
    Zimmermann, R., and P. Cerutti (1984) Active oxygen acts as a promoter of transformation in mouse embryo C3H10T1/2C18 fibroblasts. Proc. Natl. Acad. Sci., USA 81:2085–2087.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Walter J. Kozumbo
    • 1
  • Peter A. Cerutti
    • 1
  1. 1.Department of CarcinogenesisSwiss Institute for Experimental Cancer ResearchEpalinges s, LausanneSwitzerland

Personalised recommendations