Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis.
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.
Vikhanskaya
F
F
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Vignati
S
S
Beccaglia
P
P
Ottoboni
C
C
Russo
P
P
D'Incalci
M
M
Broggini
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007211:Indoles; D008938:Mitosis / Q000187:drug effects*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017239:Paclitaxel / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000086082:Viroporin Proteins
D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D007211:Indoles; D015689:Oncogene Protein p21(ras); D009856:Oncogene Proteins, Viral; D017239:Paclitaxel; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C007293:DAPI; C505407:CASP3 protein, human