Cell-cycle arrest and p53 accumulation induced by geldanamycin in human ovarian tumour cells

A J McIlwrath, V G Brunton, R Brown

Research output: Contribution to journalArticlepeer-review

Abstract

We have analysed the cell-cycle arrests and cytotoxicity of the A2780 human ovarian cell line in response to geldanamycin, a benzoquinoid ansamycin that can inhibit tyrosine kinases. Geldanamycin causes a dose-dependent G2 arrest and reversible inhibition of entry into the S phase in A2780 cells. After a 3-h exposure to 0.1 microM geldanamycin, the cells show an increase in accumulation of p53 protein that is maximal at 24 h after drug exposure. Increased p53 levels can be induced in cells by DNA-damaging agents; however, using alkaline elution and sister chromatid exchange assays we detect no DNA damage induced by geldanamycin. Using dominant negative mutant TP53 transfectants of A2780 we have analysed the possible dependence of geldanamycin-induced cell-cycle arrests on the presence of functional p53. We observe no difference in cell-cycle arrests in mutant p53 transfectants known to have the p53-DNA damage-response pathway inactivated as compared with vector-alone controls. Similarly, we observe no difference in clonogenic resistance to the cytotoxicity of geldanamycin in these cells. These results suggest that geldanamycin can induce increased p53 protein by a mechanism not involving DNA damage. Furthermore, the cell-cycle arrests and cytotoxic effects of geldanamycin in these cells are not mediated by p53-dependent pathways.
Original languageEnglish
Pages (from-to)423-8
Number of pages6
JournalCancer chemotherapy and pharmacology
Volume37
Issue number5
Publication statusPublished - 1996

Keywords

  • Antibiotics, Antineoplastic
  • Benzoquinones
  • Cell Cycle
  • Cell Survival
  • DNA Damage
  • DNA, Neoplasm
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Flow Cytometry
  • Humans
  • Interphase
  • Lactams, Macrocyclic
  • Ovarian Neoplasms
  • Quinones
  • S Phase
  • Sister Chromatid Exchange
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53

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