The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells
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- 作者：Ying-Hsi Lin ; Bert Yu-Hung Chen…
- 关键词：Akt inhibitor MK ; 2206 ; PI3K/Akt signaling pathway ; Paclitaxel (Taxol) ; Cisplatin ; Ovarian cancer
- 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
- 出版年：2015
- 出版时间：January 2015
- 年：2015
- 卷：388
- 期：1
- 页码：19-31
- 全文大小：1,947 KB
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Bert Yu-Hung Chen (1)
Wei-Ting Lai (1)
Shao-Fu Wu (1)
Jih-Hwa Guh (1)
Ann-Lii Cheng (2)
Lih-Ching Hsu (1)
1. School of Pharmacy, National Taiwan University, No. 33, Linsen S. Road, Taipei, 10050, Taiwan
2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biomedicine
Pharmacology and Toxicology
Neurosciences- 出版者：Springer Berlin / Heidelberg
- ISSN：1432-1912
- 作者单位：Ying-Hsi Lin (1)
文摘
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.