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Transformed and Tumor-derived Human Cells Exhibit Preferential Sensitivity to the Thiol Antioxidants, N-Acetyl Cysteine and Penicillamine

Departments of Therapeutic Radiology [P. A. H., D. E. B.] and Genetics [D. E. B.], and Yale Comprehensive Cancer Center [P. A. H., D. E. B.], Yale University School of Medicine, New Haven, Connecticut 06520-8040, and Departments of Microbiology & Molecular Genetics and Biochemistry & Molecular Biology, Carcinogenesis Laboratory, Food Safety and Toxicology Building, Michigan State University, East Lansing, Michigan 48824-1316 [S. O., J. J. M.]

Thiol antioxidants, typified by N-acetyl cysteine, are known to induce p53-dependent apoptosis in transformed mouse embryo fibroblasts but not in normal mouse embryo fibroblasts. We now report that this is also the case for human cells. First, we used an isogenic fibroblast cell lineage exhibiting progressive stages of transformation, from primary derived cells to v-MYC immortalized to tumorigenic. At the immortalization stage, cells became 12- and 480-fold more sensitive to the thiol antioxidants N-acetyl cysteine (NAC) and penicillamine (PEN), respectively. Although immortalization of these cells was associated with v-MYC expression, overexpression of MYC was not sufficient for sensitizing these cells to antioxidants. To test whether sensitivity to antioxidants is a general property of immortalized human cells, including fully transformed cells, 12 tumor-derived cell lines were treated with PEN, the more potent of the two antioxidants. Ten of 11 caspase-proficient tumor cell lines underwent apoptosis after treatment, whereas primary fibroblasts and keratinocytes were resistant. The difference between normal and transformed cells was apparent whether the assay used measured caspase 3 activation, Annexin V binding, or cell viability. Tumor cell lines containing wild-type p53 were more sensitive than p53-null cell lines. The requirement for p53 was tested using the p53 inhibitor, pifithrin-, or using stable transfectants of a v-MYC-immortalized, telomerase-positive cell line that expresses HPV16 E6 to bind and degrade p53. In the latter case, 80% of the PEN-induced apoptosis was dependent on the presence of wild-type p53. These studies suggest that treatment with thiol-containing antioxidants, such as PEN, may offer a useful approach for preferential induction of apoptosis in preneoplastic and neoplastic cells.

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