A peroxisome proliferator-activated receptor-γ agonist and the p53 rescue drug CP-31398 inhibit the spontaneous immortalization of breast epithelial cells

Brittney Shea Herbert, Virginia P. Pearce, Linda S. Hynan, Denise M. LaRue, Woodring E. Wright, Levy Kopelovich, Jerry W. Shay

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1914-1919
Number of pages6
JournalCancer Research
Volume63
Issue number8
StatePublished - Apr 15 2003

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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