Antioxidant action via p53-mediated apoptosis.
The biological effects of antioxidants are often considered in terms of their effects on oxygen or lipid radicals. However, antioxidants can also exert their effects through altering the cellular redox potential. Herein, we report that sulfur-containing antioxidants such as N-acetylcysteine and dimercaptopropanol induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells. In contrast, chain-breaking antioxidants such as vitamin E lacked this activity. An increased glutathione level was not required for apoptosis; however, all apoptosis-inducing antioxidants elevated the total cellular thiol levels. Antioxidant-induced apoptosis required the p53 tumor suppressor gene. N-Acetylcysteine elevated p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation rather than by altering the protein stability. The p53 induction occurred in normal cells. These observations indicate a redox sensor for p53 induction in vivo, with additional transformation-specific information being required for apoptosis. Manipulating p53-dependent apoptosis with nontoxic antioxidants may have a direct clinical application.
Liu
M
M
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Pelling
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JC
Ju
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Chu
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Brash
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D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D004112:Dimercaprol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000032:analysis; D051379:Mice; D010084:Oxidation-Reduction; D011761:Pyrrolidonecarboxylic Acid; D013438:Sulfhydryl Compounds / Q000032:analysis; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53; D004112:Dimercaprol; D014810:Vitamin E; D019328:Buthionine Sulfoximine; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid