Inhibition of the induction of cancer by antioxidants
1University of Texas, M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78757, USA.
Abstract:
Many different antioxidants have been shown to inhibit the induction of cancer by a wide variety of chemical carcinogens and/or radiation at many target sites in mice, rats, and hamsters. Evidence is accumulating that suggests that free radicals are important in all stages of chemical carcinogenesis. Both carcinogens and tumor promoters have also been shown to decrease the cellular activity of superoxide dismutase and catalase. A number of antioxidants and related compounds were tested to determine if they would inhibit either skin tumor initiation, promotion, and/or progression. In terms of skin tumor initiation, BHT, vitamin E and C and CuDIPS have been found to inhibit DMBA skin tumor initiation by approximately 50%. The mechanism of action of these compounds appears to be related to their effect on the metabolism of DMBA, since BHT and CuDIPS do not inhibit the initiating activity of BP-diol-epoxide and MNNG. Although several antioxidants do inhibit skin tumor initiation by procarcinogens, antioxidants are in general much more effective inhibitors of skin tumor promotion. BHT, BHA, parahydroxyanisole, disulfiran, and vitamin E and C inhibit skin tumor promotion by TPA and benzoyl peroxide by greater than 90%. We also determined the effect of free radical scavengers on the progression process. Of the agents tested glutathione and N-acyl dehydroalamines were the most effective in reducing carcinoma incidence. Diethyl maleate, a chemical that reduces glutathione levels, was effective in enhancing progression. In addition overexpression of g-glutamylt-ranspeptidase (GGT) which leads to a reduction in cellular glutathione levels also enhances progression. These results suggest that GGT has a functional role in skin tumor progression, and that a number of antioxidants are either effective inhibitors of skin tumor initiation, promotion, and/or progression.
Insights
Antioxidants can inhibit cancer development by interfering with free radicals. This study shows antioxidants are effective in preventing skin tumor initiation, promotion, and progression.
Area of Science:
- Oncology
- Biochemistry
- Free Radical Biology
Background:
- Free radicals are implicated in all stages of chemical carcinogenesis.
- Carcinogens and tumor promoters can decrease cellular antioxidant enzyme activity (superoxide dismutase, catalase).
- Antioxidants may counteract these effects, potentially inhibiting cancer development.
Purpose of the Study:
- To investigate the inhibitory effects of various antioxidants on skin tumor initiation, promotion, and progression.
- To explore the mechanisms underlying antioxidant activity in chemical carcinogenesis.
- To identify specific antioxidants effective at different stages of skin tumor development.
Main Methods:
- Testing of antioxidants including BHT, vitamins E and C, CuDIPS, BHA, parahydroxyanisole, disulfiram, glutathione, and N-acyl dehydroalamines.
- Assessment of inhibition of 7,12-dimethylbenz[a]anthracene (DMBA) skin tumor initiation.
- Evaluation of inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA) and benzoyl peroxide-induced skin tumor promotion.
- Analysis of effects on skin tumor progression, including the role of glutathione and gamma-glutamyl transpeptidase (GGT).
Main Results:
- BHT, vitamin E, vitamin C, and CuDIPS inhibited DMBA skin tumor initiation by approximately 50%.
- Antioxidants were more effective inhibitors of skin tumor promotion, with BHT, BHA, parahydroxyanisole, disulfiram, vitamin E, and vitamin C inhibiting TPA and benzoyl peroxide promotion by over 90%.
- Glutathione and N-acyl dehydroalamines were most effective in reducing carcinoma incidence during progression; diethyl maleate and GGT overexpression enhanced progression by reducing glutathione levels.
Conclusions:
- Antioxidants demonstrate significant inhibitory effects on skin tumor initiation, promotion, and progression.
- The efficacy of antioxidants varies depending on the stage of carcinogenesis and the specific carcinogen/promoter involved.
- Modulating glutathione levels and GGT activity may represent therapeutic strategies for inhibiting skin tumor progression.
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