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p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection.

Lee EJ, Gerhold M, Palmer MW, Christen RD - Br. J. Cancer (2003)

Bottom Line: In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death.Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis.In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.British

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cancer Center, University of California San Diego, La Jolla 92093, USA.

ABSTRACT
To determine the role of p53 protein on the cellular effects of amifostine, we used molecularly engineered HCT116 colon cancer cells in which the p53 gene was inactivated by targeted homologous recombination or p53 protein was degraded by high-level expression of papillomavirus E6 protein. Amifostine induced a G1 arrest and protected against paclitaxel toxicity in p53-proficient but not in p53-deficient cells. In the absence of p53 protein, amifostine enhanced the cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death. Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis. Amifostine induced the expression of p53 protein in p53-proficient cells and the expression of p21 protein in both p53-proficient and -deficient cells. These findings indicate that amifostine-induced G1 arrest and cytoprotection are mediated via a pathway that is dependent on p53 protein and that amifostine-induced expression of p21 protein is not sufficient to sustain a G1 arrest or to mediate cytoprotection. In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.British

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Effect of p53 protein on amifostine-induced apoptosis. HCT116 cells were exposed to amifostine for 24 h, and the fraction of apoptotic cells was determined by supravital fluorescence microscopy at 72 and 96 h after the beginning of exposure to amifostine. Upper panel: white columns, HCT116/p53+/+ cells; black columns, HCT116/p53−/− cells; shaded columns, HCT116/E6 cells. Lower panel: white columns, HCT116+ch3 cells; shaded columns, HCT116+ch3/E6 cells. Columns and bars represent mean±s.d. of three independent experiments each performed with triplicate cultures.
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fig2: Effect of p53 protein on amifostine-induced apoptosis. HCT116 cells were exposed to amifostine for 24 h, and the fraction of apoptotic cells was determined by supravital fluorescence microscopy at 72 and 96 h after the beginning of exposure to amifostine. Upper panel: white columns, HCT116/p53+/+ cells; black columns, HCT116/p53−/− cells; shaded columns, HCT116/E6 cells. Lower panel: white columns, HCT116+ch3 cells; shaded columns, HCT116+ch3/E6 cells. Columns and bars represent mean±s.d. of three independent experiments each performed with triplicate cultures.

Mentions: Supravital fluorescence microscopy was used to quantitate apoptotic cells (Figure 2Figure 2


p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection.

Lee EJ, Gerhold M, Palmer MW, Christen RD - Br. J. Cancer (2003)

Effect of p53 protein on amifostine-induced apoptosis. HCT116 cells were exposed to amifostine for 24 h, and the fraction of apoptotic cells was determined by supravital fluorescence microscopy at 72 and 96 h after the beginning of exposure to amifostine. Upper panel: white columns, HCT116/p53+/+ cells; black columns, HCT116/p53−/− cells; shaded columns, HCT116/E6 cells. Lower panel: white columns, HCT116+ch3 cells; shaded columns, HCT116+ch3/E6 cells. Columns and bars represent mean±s.d. of three independent experiments each performed with triplicate cultures.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376343&req=5

fig2: Effect of p53 protein on amifostine-induced apoptosis. HCT116 cells were exposed to amifostine for 24 h, and the fraction of apoptotic cells was determined by supravital fluorescence microscopy at 72 and 96 h after the beginning of exposure to amifostine. Upper panel: white columns, HCT116/p53+/+ cells; black columns, HCT116/p53−/− cells; shaded columns, HCT116/E6 cells. Lower panel: white columns, HCT116+ch3 cells; shaded columns, HCT116+ch3/E6 cells. Columns and bars represent mean±s.d. of three independent experiments each performed with triplicate cultures.
Mentions: Supravital fluorescence microscopy was used to quantitate apoptotic cells (Figure 2Figure 2

Bottom Line: In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death.Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis.In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.British

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Cancer Center, University of California San Diego, La Jolla 92093, USA.

ABSTRACT
To determine the role of p53 protein on the cellular effects of amifostine, we used molecularly engineered HCT116 colon cancer cells in which the p53 gene was inactivated by targeted homologous recombination or p53 protein was degraded by high-level expression of papillomavirus E6 protein. Amifostine induced a G1 arrest and protected against paclitaxel toxicity in p53-proficient but not in p53-deficient cells. In the absence of p53 protein, amifostine enhanced the cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death. Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis. Amifostine induced the expression of p53 protein in p53-proficient cells and the expression of p21 protein in both p53-proficient and -deficient cells. These findings indicate that amifostine-induced G1 arrest and cytoprotection are mediated via a pathway that is dependent on p53 protein and that amifostine-induced expression of p21 protein is not sufficient to sustain a G1 arrest or to mediate cytoprotection. In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.British

Show MeSH
Related in: MedlinePlus