Inactivation of p53 in a Human Ovarian Cancer Cell Line Increases the Sensitivity to Paclitaxel by Inducing G2/M Arrest and Apoptosis

• Published in: Experimental cell research Vol. 241; no. 1; pp. 96 - 101
• Main Authors: Vikhanskaya, Faina, Vignati, Sara, Beccaglia, Patrizia, Ottoboni, Cristina, Russo, Patrizia, D'Incalci, Maurizio, Broggini, Massimo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.05.1998
• Subjects: 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
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.1998.4018

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.