The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
388
Journal Issue
1
Pages
19-31
Date Issued
2014
Author(s)
Abstract
Abnormalities in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway are commonly observed in human cancers and contribute to chemotherapy resistance. Combination therapy, involving the use of molecular targeted agents and traditional cytotoxic drugs, may represent a promising strategy to lower resistance and enhance cytotoxicity. Here, we demonstrate the efficacy of an Akt inhibitor, MK-2206, in increasing the cytotoxic effect of either paclitaxel (Taxol) or cisplatin against the ovarian cancer cell lines SKOV3 (with constitutively active Akt) and ES2 (with inactive Akt). Sequential treatment of Taxol or cisplatin, followed by MK-2206, induced a synergistic inhibition of cell proliferation and effectively promoted cell death, either by inhibiting the phosphorylation of Akt and its downstream effectors 4E-BP1 and p70S6K in SKOV3 cells or by restoring p53 levels, which were downregulated after Taxol or cisplatin treatment, in ES2 cells. Combination treatment also downregulated the pro-survival protein Bcl-2 in both SKOV3 and ES2 cells, which may have contributed to cell death. In addition, we discovered that Taxol/MK-2206 or cisplatin/MK-2206 combination treatment resulted in significant enhancement of intracellular reactive oxygen species (ROS) induced by MK-2206, in both SKOV3 and ES2 cells; however, MK-2206-induced growth inhibition was reversed by a ROS scavenger only in ES2 cells. MK-2206 also suppressed DNA repair, particularly in SKOV3 cells. Taken together, our results demonstrate that the Akt inhibitor MK-2206 enhances the efficacy of cytotoxic agents in both Akt-active and Akt-inactive ovarian cancer cells but through different mechanisms. ? 2014 Springer-Verlag Berlin Heidelberg.
SDGs
Other Subjects
8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; cisplatin; paclitaxel; protein bcl 2; protein kinase B; protein p53; reactive oxygen metabolite; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; antineoplastic agent; cisplatin; fused heterocyclic rings; paclitaxel; protein bcl 2; protein kinase B; protein kinase inhibitor; protein p53; reactive oxygen metabolite; Article; cell death; cell proliferation; DNA repair; down regulation; drug cytotoxicity; drug efficacy; drug mechanism; drug potentiation; female; growth inhibition; human; human cell; ovarian cancer cell line; ovary cancer; protein phosphorylation; antagonists and inhibitors; cell survival; drug effects; metabolism; Ovarian Neoplasms; tumor cell line; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Drug Synergism; Female; Heterocyclic Compounds, 3-Ring; Humans; Ovarian Neoplasms; Paclitaxel; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Tumor Suppressor Protein p53
Type
journal article