Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis

Exp Cell Res. 1998 May 25;241(1):96-101. doi: 10.1006/excr.1998.4018.

Abstract

Paclitaxel-induced cytotoxicity, cell cycle perturbation, and apoptosis were determined in a human ovarian cancer cell line expressing wt p53 (A2780) and in a subclone (A2780/E6) obtained upon transfection with the product of the E6 gene of the human papilloma virus HPV16. The inactivation of wt p53 in A2780/E6 was verified by measuring the inability of the clone to induce p53 and p21 expression after paclitaxel treatment. The p53-negative clone (A2780/E6) was approximately 50-fold more sensitive to paclitaxel than wt p53-expressing A2780 cells. This increased sensitivity was related to the ability of paclitaxel to induce a strong arrest of cells in the G2/M phase of the cell cycle in A2780/E6 but not in A2780 cells. This different cell cycle arrest was accompanied by increased frequency of paclitaxel-induced p53-independent apoptosis. Initial studies on proteases activation tend to exclude a direct role of ICE and CPP32 in the induction of apoptosis in these cells and show a paclitaxel-dependent increase in FLICE levels, whose biological relevance is however at present not defined.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Nucleus / chemistry
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / metabolism
  • Female
  • G2 Phase / drug effects*
  • HL-60 Cells / drug effects
  • HL-60 Cells / enzymology
  • Humans
  • Indoles
  • Mitosis / drug effects*
  • Oncogene Protein p21(ras) / metabolism
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / physiology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / physiopathology
  • Paclitaxel / pharmacology*
  • Recombinant Proteins / genetics
  • Sensitivity and Specificity
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • Indoles
  • Oncogene Proteins, Viral
  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • oncogene protein E5, Human papillomavirus type 16
  • DAPI
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases
  • Oncogene Protein p21(ras)
  • Paclitaxel