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Antioxidant Action via p53-mediated Apoptosis¹

Departments of Therapeutic Radiology [M. L., D. E. B.] and Genetics [D. E. B.], Yale University School of Medicine, New Haven, Connecticut 06520; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160 [J. C. P.]; and Departments of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine and VA Connecticut Healthcare System, New Haven, Connecticut 06520 [J. J., E. C.]

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.

¹ Supported by NIH Grants CA55737 (to D. E. B.), CA40847 (to J. C. P.), and CA16359 (to E. C.) and the Yale Cancer Center Flow Cytometry Shared Resource, and by the Leslie H. Warner Postdoctoral Fellowship in Cancer Research (to M. L.).

² To whom requests for reprints should be addressed, at Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040. Fax: (203) 785-6309; E-mail: douglas.brash@yale.edu.

Received 11/18/97. Accepted 2/18/98.

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