Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1984 Apr;81(7):2085–2087. doi: 10.1073/pnas.81.7.2085

Active oxygen acts as a promoter of transformation in mouse embryo C3H/10T1/2/C18 fibroblasts.

R Zimmerman, P Cerutti
PMCID: PMC345441  PMID: 6425826

Abstract

There is much evidence from in vivo and in vitro carcinogenesis studies that active oxygen species play a role in tumor promotion. We tested directly whether superoxide produced extracellularly by xanthine-xanthine oxidase (X-XO) has the capacity to promote initiated mouse embryo C3H/10T1/2 fibroblasts. Cell cultures initiated with either 137Cs gamma-rays or benzo[a]pyrene diol epoxide I were found to transform 3-30 times more effectively when subsequently treated daily for 3 weeks with nontoxic doses of X-XO. Scavengers of active oxygen radicals such as superoxide dismutase or superoxide dismutase in combination with catalase reduced the frequency of appearance of transformed foci by 3-25 times when compared to cultures receiving X-XO alone. These results show that active oxygen species such as superoxide and H2O2 can act in a promotional manner that mimics the effects of the mouse skin promoter phorbol 12-myristate 13-acetate in this system. X-XO also acted as a weak complete carcinogen.

Full text

PDF
2085

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ames B. N., Cathcart R., Schwiers E., Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858–6862. doi: 10.1073/pnas.78.11.6858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ames B. N. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science. 1983 Sep 23;221(4617):1256–1264. doi: 10.1126/science.6351251. [DOI] [PubMed] [Google Scholar]
  3. Amstad P., Cerutti P. DNA binding of aflatoxin B1 by co-oxygenation in mouse embryo fibroblasts C3H/10T1/2. Biochem Biophys Res Commun. 1983 May 16;112(3):1034–1040. doi: 10.1016/0006-291x(83)91722-9. [DOI] [PubMed] [Google Scholar]
  4. Benedict W. F., Wheatley W. L., Jones P. A. Inhibition of chemically induced morphological transformation and reversion of the transformed phenotype of ascorbic acid in C3H/10T 1/2 cells. Cancer Res. 1980 Aug;40(8 Pt 1):2796–2801. [PubMed] [Google Scholar]
  5. Borek C., Troll W. Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1304–1307. doi: 10.1073/pnas.80.5.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cerutti P. A. Effects of ionizing radiation on mammalian cells. Naturwissenschaften. 1974 Feb;61(2):51–59. doi: 10.1007/BF00596195. [DOI] [PubMed] [Google Scholar]
  7. Diamond L., O'Brien T. G., Baird W. M. Tumor promoters and the mechanism of tumor promotion. Adv Cancer Res. 1980;32:1–74. doi: 10.1016/s0065-230x(08)60360-7. [DOI] [PubMed] [Google Scholar]
  8. Emerit I., Cerutti P. A. Tumor promoter phorbol 12-myristate 13-acetate induces a clastogenic factor in human lymphocytes. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7509–7513. doi: 10.1073/pnas.79.23.7509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Emerit I., Cerutti P. A. Tumour promoter phorbol-12-myristate-13-acetate induces chromosomal damage via indirect action. Nature. 1981 Sep 10;293(5828):144–146. doi: 10.1038/293144a0. [DOI] [PubMed] [Google Scholar]
  10. Emerit I., Keck M., Levy A., Feingold J., Michelson A. M. Activated oxygen species at the origin of chromosome breakage and sister-chromatid exchanges. Mutat Res. 1982 Feb;103(2):165–172. doi: 10.1016/0165-7992(82)90024-0. [DOI] [PubMed] [Google Scholar]
  11. Emerit I., Levy A., Cerutti P. Suppression of tumor promoter phorbolmyristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism. Mutat Res. 1983 Aug;110(2):327–335. doi: 10.1016/0027-5107(83)90149-5. [DOI] [PubMed] [Google Scholar]
  12. Fernandez-Pol J. A., Hamilton P. D., Klos D. J. Correlation between the loss of the transformed phenotype and an increase in superoxide dismutase activity in a revertant subclone of sarcoma virus-infected mammalian cells. Cancer Res. 1982 Feb;42(2):609–617. [PubMed] [Google Scholar]
  13. Friedman J., Cerutti P. The induction of ornithine decarboxylase by phorbol 12-myristate 13-acetate or by serum is inhibited by antioxidants. Carcinogenesis. 1983 Nov;4(11):1425–1427. doi: 10.1093/carcin/4.11.1425. [DOI] [PubMed] [Google Scholar]
  14. Ito A., Watanabe H., Naito M., Naito Y. Induction of duodenal tumors in mice by oral administration of hydrogen peroxide. Gan. 1981 Feb;72(1):174–175. [PubMed] [Google Scholar]
  15. Kellogg E. W., 3rd, Fridovich I. Superoxide, hydrogen peroxide, and singlet oxygen in lipid peroxidation by a xanthine oxidase system. J Biol Chem. 1975 Nov 25;250(22):8812–8817. [PubMed] [Google Scholar]
  16. Kennedy A. R., Mondal S., Heidelberger C., Little J. B. Enhancement of X-ray transformation by 12-O-tetradecanoyl-phorbol-13-acetate in a cloned line of C3H mouse embryo cells. Cancer Res. 1978 Feb;38(2):439–443. [PubMed] [Google Scholar]
  17. Kensler T. W., Bush D. M., Kozumbo W. J. Inhibition of tumor promotion by a biomimetic superoxide dismutase. Science. 1983 Jul 1;221(4605):75–77. doi: 10.1126/science.6857269. [DOI] [PubMed] [Google Scholar]
  18. Kozumbo W. J., Seed J. L., Kensler T. W. Inhibition by 2(3)-tert-butyl-4-hydroxyanisole and other antioxidants of epidermal ornithine decarboxylase activity induced by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 1983 Jun;43(6):2555–2559. [PubMed] [Google Scholar]
  19. Leuthauser S. W., Oberley L. W., Oberley T. D., Sorenson J. R., Ramakrishna K. Antitumor effect of a copper coordination compound with superoxide dismutase-like activity. J Natl Cancer Inst. 1981 Jun;66(6):1077–1081. doi: 10.1093/jnci/66.6.1077. [DOI] [PubMed] [Google Scholar]
  20. Levin D. E., Hollstein M., Christman M. F., Schwiers E. A., Ames B. N. A new Salmonella tester strain (TA102) with A X T base pairs at the site of mutation detects oxidative mutagens. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7445–7449. doi: 10.1073/pnas.79.23.7445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McCord J. M., Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969 Nov 25;244(22):6049–6055. [PubMed] [Google Scholar]
  22. Mondal S., Brankow D. W., Heidelberger C. Two-stage chemical oncogenesis in cultures of C3H/10T1/2 cells. Cancer Res. 1976 Jul;36(7 Pt 1):2254–2260. [PubMed] [Google Scholar]
  23. Mondal S., Heidelberger C. Transformation of C3H/10T1/2CL8 mouse embryo fibroblasts by ultraviolet irradiation and a phorbol ester. Nature. 1976 Apr 22;260(5553):710–711. doi: 10.1038/260710a0. [DOI] [PubMed] [Google Scholar]
  24. Moody C. S., Hassan H. M. Mutagenicity of oxygen free radicals. Proc Natl Acad Sci U S A. 1982 May;79(9):2855–2859. doi: 10.1073/pnas.79.9.2855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Novi A. M. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science. 1981 May 1;212(4494):541–542. doi: 10.1126/science.6782675. [DOI] [PubMed] [Google Scholar]
  26. Prasad K. N., Edwards-Prasad J. Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res. 1982 Feb;42(2):550–555. [PubMed] [Google Scholar]
  27. Reddy J. K., Azarnoff D. L., Hignite C. E. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature. 1980 Jan 24;283(5745):397–398. doi: 10.1038/283397a0. [DOI] [PubMed] [Google Scholar]
  28. Roti J. L., Cerutti P. A. Letter: Gamma-ray induced thymine damage in mammalian cells. Int J Radiat Biol Relat Stud Phys Chem Med. 1974 Apr;25(4):413–417. doi: 10.1080/09553007414550491. [DOI] [PubMed] [Google Scholar]
  29. Slaga T. J., Klein-Szanto A. J., Triplett L. L., Yotti L. P., Trosko K. E. Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound. Science. 1981 Aug 28;213(4511):1023–1025. doi: 10.1126/science.6791284. [DOI] [PubMed] [Google Scholar]
  30. Takigawa M., Verma A. K., Simsiman R. C., Boutwell R. K. Polyamine biosynthesis and skin tumor promotion: inhibition of 12-O-tetradecanoylphorbol-13-acetate-promoted mouse skin tumor formation by the irreversible inhibitor of ornithine decarboxylase alpha-difluoromethylornithine. Biochem Biophys Res Commun. 1982 Apr 14;105(3):969–976. doi: 10.1016/0006-291x(82)91065-8. [DOI] [PubMed] [Google Scholar]
  31. Totter J. R. Spontaneous cancer and its possible relationship to oxygen metabolism. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1763–1767. doi: 10.1073/pnas.77.4.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weeks C. E., Herrmann A. L., Nelson F. R., Slaga T. J. alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6028–6032. doi: 10.1073/pnas.79.19.6028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Weitberg A. B., Weitzman S. A., Destrempes M., Latt S. A., Stossel T. P. Stimulated human phagocytes produce cytogenetic changes in cultured mammalian cells. N Engl J Med. 1983 Jan 6;308(1):26–30. doi: 10.1056/NEJM198301063080107. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES