© 1996 Oxford University Press
research-article |
Antioxidants inhibit the enhancement of malignant cell transformation induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin
Department of Toxicology, University of Hamburg Medical School Grindelallee 117, D-20146 Hamburg, Germany
Department of Toxicology and Environmental Medicine of the Fraunhofer Society Grindelallee 117, D-20146 Hamburg, Germany
The mechanisms of the tumor promoting activity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) were studied using as in vitro model the enhancement (‘promotion’) of malignant transformation ofC3H/M2 mouse fibroblasts induced by N-methyl-N‘-nitro-N-nitrosoguanidine or 3-methylcholanthrene. In this assay, the promoting effect of TCDD was maximal at a very low concentration of 1.5 pM and was comparable to the effect of the reference tumor promoter, 12-O-tetradecanoylphorbol–13-acetate (TPA, 0.25 µg/ml). The role of reactive oxygen species in the promoting action was investigated: mannitol, a scavenger of hydroxyl radicals, or antioxidants, i.e. ascorbic acid plus 
-tocopherol, abolishedthe in vitro promoting effects of TPA and TCDD. Furthermore, the involvement of protein kinase C (PKC) activation was studied: the protein kinase inhibitor H-7 markedly reduced the in vitro promoting activity of TPA but did not affect the promotion by TCDD. In accord with these results, TPA, but not TCDD, enhanced the PKC activityin C3H/M2 fibroblasts. Since the TPA-mediated activation of PKC was not affected by ascorbate plus -tocopherol, it is concluded that the antioxidants interfere with tumor promotion at a step beyond PKC activation. Thus, the results suggest that the enhancement of malignant cell transformation by TPA and TCDD is dependent on a common mechanism, possibly induced by oxygen radicals, and, in addition, on further mechanisms that may involve agent-specific signalling pathways (e.g. PKC activation by TPA).
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Chopra, A. M. Dharmarajan, G. Meiss, and D. Schrenk Inhibition of UV-C Light-Induced Apoptosis in Liver Cells by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Toxicol. Sci., September 1, 2009; 111(1): 49 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.J. Hodges, T.C. Orton, A.J. Strain, and J.K. Chipman Potentiation of epidermal growth factor-induced DNA synthesis in rat hepatocytes by phenobarbitone: possible involvement of oxidative stress and kinase activation Carcinogenesis, November 1, 2000; 21(11): 2041 - 2047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wolfle, S. Marotzki, D. Dartsch, W. Schafer, and H. Marquardt Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo- p-dioxin Carcinogenesis, January 1, 2000; 21(1): 15 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-P. Huang, A. Peng, M. Z. Hossain, Y. Fan, A. Jagdale, and A. L. Boynton Tumor promotion by hydrogen peroxide in rat liver epithelial cells Carcinogenesis, March 1, 1999; 20(3): 485 - 492. [Abstract] [Full Text] [PDF]
|
|