Modulation of cisplatinum cytotoxicity by p53: Effect of p53-mediated apoptosis and DNA repair Journal Article


Authors: Fan, J.; Bertino, J. R.
Article Title: Modulation of cisplatinum cytotoxicity by p53: Effect of p53-mediated apoptosis and DNA repair
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.
Keywords: controlled study; human cell; cisplatin; antineoplastic agents; dna damage; cell division; dna repair; protein bcl 2; apoptosis; gene expression; down-regulation; tumor cells, cultured; protein p53; regulatory mechanism; dna, neoplasm; tumor suppressor protein p53; gene control; gene induction; drug cytotoxicity; tetracycline; cell protection; drug sensitivity; proto-oncogene proteins c-bcl-2; culture media; humans; human; priority journal; article
Journal Title: Molecular Pharmacology
Volume: 56
Issue: 5
ISSN: 0026-895X
Publisher: The American Society for Pharmacology and Experimental Therapeutics  
Date Published: 1999-11-01
Start Page: 966
End Page: 972
Language: English
PUBMED: 10531402
PROVIDER: scopus
DOI: 10.1124/mol.56.5.966
DOI/URL:
Notes: Article -- Export Date: 16 August 2016 -- Source: Scopus
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MSK Authors
  1. Jianguo Fan
    29 Fan
  2. Joseph Bertino
    259 Bertino