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A novel form of constitutively active farnesylated Akt1 prevents mammary epithelial cells from anoikis and suppresses chemotherapy-induced apoptosis.

Schmidt M, Hövelmann S, Beckers TL - Br. J. Cancer (2002)

Bottom Line: Enigneered MCF10A cells were rendered resistant towards apoptosis resulting from loss of cellular substrate attachment (anoikis).A profoundly decreased sensitivity towards Mitoxantrone and cisplatin was observed in cells expressing farnesylated Akt.No significant difference in sensitivity however was observed upon treatment with cell cycle specific chemotherapeutic agents like paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: ASTA Medica Oncology, Weismüllerstr. 45, D-60314 Frankfurt, Germany. mathias.schmidt@altanapharma.com

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Chemoresistance of A549 human lung cancer cells expressing farnesylated Akt1. Control transfected A549 cells or A549-Akt1 cells were seeded in 96-well plates in medium containing 0.5% serum. Twenty-four hours later the cells were treated with different concentrations of cisplatin (left) or mitoxantrone (right) as indicated and incubated for another 72 h at 37°C. Cell viability was then determined with a standard XTT assay as described in Materials and Methods. Values are the mean of at least three independent experiments.
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fig5: Chemoresistance of A549 human lung cancer cells expressing farnesylated Akt1. Control transfected A549 cells or A549-Akt1 cells were seeded in 96-well plates in medium containing 0.5% serum. Twenty-four hours later the cells were treated with different concentrations of cisplatin (left) or mitoxantrone (right) as indicated and incubated for another 72 h at 37°C. Cell viability was then determined with a standard XTT assay as described in Materials and Methods. Values are the mean of at least three independent experiments.

Mentions: Intrinsic or acquired resistance towards chemotherapy is the most important limitation of current treatment options in cancer. While active transport mechanisms have been described to shuffle chemotherapeutic agents out of cells, other mechanisms are suggested that effectively suppress apoptotic pathways in tumour cells. Although Akt has been described in the suppression of a variety of apoptotic stimuli, relatively little is known about the modulation of chemosensitivity by Akt1. We therefore compared the chemosensitivity of control transfected A549 human NSCLC cells vs A549 cells expressing farnesylated Akt1 towards a regimen of clinically applied chemotherapeutics. The viability of the cells after incubation with the substances for 72 h was determined with a standard XTT assay as described in Materials and Methods. A549 cells expressing constitutively active Akt1 displayed an approximately 10-fold decreased sensitivity towards the DNA alkylating agent Mitoxantrone as compared to control cells (IC50 0.2 μM vs 0.02 μM, respectively). A more than two-fold decreased sensitivity was observed upon treatment of the cells with the DNA alkylating agent cis-platin (Figure 5Figure 5


A novel form of constitutively active farnesylated Akt1 prevents mammary epithelial cells from anoikis and suppresses chemotherapy-induced apoptosis.

Schmidt M, Hövelmann S, Beckers TL - Br. J. Cancer (2002)

Chemoresistance of A549 human lung cancer cells expressing farnesylated Akt1. Control transfected A549 cells or A549-Akt1 cells were seeded in 96-well plates in medium containing 0.5% serum. Twenty-four hours later the cells were treated with different concentrations of cisplatin (left) or mitoxantrone (right) as indicated and incubated for another 72 h at 37°C. Cell viability was then determined with a standard XTT assay as described in Materials and Methods. Values are the mean of at least three independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2376180&req=5

fig5: Chemoresistance of A549 human lung cancer cells expressing farnesylated Akt1. Control transfected A549 cells or A549-Akt1 cells were seeded in 96-well plates in medium containing 0.5% serum. Twenty-four hours later the cells were treated with different concentrations of cisplatin (left) or mitoxantrone (right) as indicated and incubated for another 72 h at 37°C. Cell viability was then determined with a standard XTT assay as described in Materials and Methods. Values are the mean of at least three independent experiments.
Mentions: Intrinsic or acquired resistance towards chemotherapy is the most important limitation of current treatment options in cancer. While active transport mechanisms have been described to shuffle chemotherapeutic agents out of cells, other mechanisms are suggested that effectively suppress apoptotic pathways in tumour cells. Although Akt has been described in the suppression of a variety of apoptotic stimuli, relatively little is known about the modulation of chemosensitivity by Akt1. We therefore compared the chemosensitivity of control transfected A549 human NSCLC cells vs A549 cells expressing farnesylated Akt1 towards a regimen of clinically applied chemotherapeutics. The viability of the cells after incubation with the substances for 72 h was determined with a standard XTT assay as described in Materials and Methods. A549 cells expressing constitutively active Akt1 displayed an approximately 10-fold decreased sensitivity towards the DNA alkylating agent Mitoxantrone as compared to control cells (IC50 0.2 μM vs 0.02 μM, respectively). A more than two-fold decreased sensitivity was observed upon treatment of the cells with the DNA alkylating agent cis-platin (Figure 5Figure 5

Bottom Line: Enigneered MCF10A cells were rendered resistant towards apoptosis resulting from loss of cellular substrate attachment (anoikis).A profoundly decreased sensitivity towards Mitoxantrone and cisplatin was observed in cells expressing farnesylated Akt.No significant difference in sensitivity however was observed upon treatment with cell cycle specific chemotherapeutic agents like paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: ASTA Medica Oncology, Weismüllerstr. 45, D-60314 Frankfurt, Germany. mathias.schmidt@altanapharma.com

Show MeSH
Related in: MedlinePlus