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
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects*
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Caspase 3
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Caspases*
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Cell Death / drug effects
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Cell Death / physiology
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Cell Nucleus / chemistry
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cysteine Endopeptidases / drug effects
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Cysteine Endopeptidases / metabolism
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Female
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G2 Phase / drug effects*
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HL-60 Cells / drug effects
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HL-60 Cells / enzymology
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Humans
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Indoles
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Mitosis / drug effects*
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Oncogene Protein p21(ras) / metabolism
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / physiology
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / physiopathology
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Paclitaxel / pharmacology*
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Recombinant Proteins / genetics
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Sensitivity and Specificity
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Transfection
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Tumor Cells, Cultured / drug effects
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Antineoplastic Agents, Phytogenic
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Indoles
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Oncogene Proteins, Viral
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Recombinant Proteins
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Tumor Suppressor Protein p53
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oncogene protein E5, Human papillomavirus type 16
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DAPI
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CASP3 protein, human
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Caspase 3
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Caspases
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Cysteine Endopeptidases
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Oncogene Protein p21(ras)
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Paclitaxel