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A Peroxisome Proliferator-activated Receptor- Agonist and the p53 Rescue Drug CP-31398 Inhibit the Spontaneous Immortalization of Breast Epithelial Cells¹

Departments of Cell Biology [B-S. H., V. P. P., D. M. L., W. E. W., J. W. S.] and Psychiatry and Academic Computing Services [L. S. H.], The University of Texas Southwestern Medical Center, Dallas, Texas 75390, and CADRG, DCP, National Cancer Institute, Bethesda, Maryland 20892 [L. K.]

Cell immortalization is a critical and rate-limiting step in cancer progression. Agents that inhibit cell immortalization may have utility for novel molecular chemopreventive strategies. Preimmortal breast epithelial cells derived from a patient with the Li-Fraumeni Syndrome (LFS) can spontaneously immortalize in vitro at a measurable and reproducible frequency. In the present study, these cells were treated in vitro with low (nM) concentrations of potential and otherwise clinically validated chemopreventive agents, including several nonsteroidal anti-inflammatory drugs, rosiglitazone maleate, and the p53 rescue drug CP-31398. Rosiglitazone maleate (P < 0.05) and CP-31398 (P < 0.05) significantly inhibited the frequency of spontaneous immortalization of LFS breast epithelial cells compared with untreated controls. Nonsteroidal anti-inflammatory drugs, including specific cyclooxengenase-2 inhibitors, only moderately inhibited the spontaneous immortalization of preimmortal LFS breast epithelial cells. The significant effects of the p53 rescue drug CP-31398 correlated with the increase in cellular death induced by telomere shortening-induced DNA damage signals, including increases in p53 and p21 protein levels. Because immortalization is one step in cancer progression, these studies show the potential usefulness of a cell-based model system to screen the effects of known and potentially novel chemopreventive agents, using cell immortalization as an end point.