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Research ArticleArticle

Modulation of Cisplatinum Cytotoxicity by p53: Effect of p53-Mediated Apoptosis and DNA Repair

Jianguo Fan and Joseph R. Bertino
Molecular Pharmacology November 1999, 56 (5) 966-972; DOI: https://doi.org/10.1124/mol.56.5.966
Jianguo Fan
Program for Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York
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Joseph R. Bertino
Program for Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York
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Abstract

A stable transfectant (S2SN7) of p53-null SaOS-2 (human osteosarcoma) cells expressing wild-type p53 under the tight control of a tetracycline-responsive promoter was used to study the functional roles of p53 in cellular response to cisplatinum (CP). When cells were grown in media containing normal concentrations (10%) of serum, induction of p53 by tetracycline withdrawal resulted in an 8-fold decrease in sensitivity to CP. In contrast, when cells were grown in lower serum (1%) media, induction of p53 led to a 10-fold increase in sensitivity to CP. The p53-mediated sensitivity to CP under lower serum conditions was attributed, at least in part, to increased susceptibility of p53-mediated apoptosis. Under lower serum (0.1–1%) but not normal serum conditions, p53 induction correlated with selective down-regulation of bcl-2, an inhibitor of apoptosis. In addition, a host-cell reactivation assay showed that induction of p53 caused a significant increase in repair of CP-induced DNA damage under normal serum but not low serum conditions. These data suggest that growth conditions may modulate and possibly reverse p53-mediated CP sensitivity by altering p53-mediated gene regulation and, as a result, susceptibility to apoptosis. They also suggest that a combined effect of p53-mediated apoptosis and DNA repair may be the ultimate determinant in p53-mediated cellular resistance or sensitivity to chemotherapeutic drugs.

Footnotes

    • Received April 6, 1999.
    • Accepted July 16, 1999.
  • Send reprint requests to: Dr. Joseph R. Bertino, Molecular Pharmacology and Therapeutics, Box 78, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York, NY 10021. E-mail:bertino{at}mskcc.org

  • ↵1 Supported by U.S. Public Health Service Training Grant CA62948-02.

  • This study was supported by U.S. Public Health Service (Grant PO1-CA-47179).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Modulation of Cisplatinum Cytotoxicity by p53: Effect of p53-Mediated Apoptosis and DNA Repair

Jianguo Fan and Joseph R. Bertino
Molecular Pharmacology November 1, 1999, 56 (5) 966-972; DOI: https://doi.org/10.1124/mol.56.5.966

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Research ArticleArticle

Modulation of Cisplatinum Cytotoxicity by p53: Effect of p53-Mediated Apoptosis and DNA Repair

Jianguo Fan and Joseph R. Bertino
Molecular Pharmacology November 1, 1999, 56 (5) 966-972; DOI: https://doi.org/10.1124/mol.56.5.966
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