A novel form of constitutively active farnesylated Akt1 prevents mammary epithelial cells from anoikis and suppresses chemotherapy-induced apoptosis.
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.
Affiliation: ASTA Medica Oncology, Weismüllerstr. 45, D-60314 Frankfurt, Germany. firstname.lastname@example.orgShow MeSH
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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
Affiliation: ASTA Medica Oncology, Weismüllerstr. 45, D-60314 Frankfurt, Germany. email@example.com