| Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through up-regulation of c-Jun. | |
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MedLine Citation:
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PMID: 21610153 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: The mammalian target of rapamycin (mTOR) pathway is thought to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. The present study aimed to assess the potential to use rapamycin and anticancer agents in combination for first- and second-line chemotherapy to treat ovarian cancer.EXPERIMENTAL DESIGN: We used six ovarian serous adenocarcinoma cell lines (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, TU-OS-4) in this study. We treated the cells with rapamycin and anticancer agents, then assessed cell viability, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of these drug combinations on survival in nude mouse xenograft models.RESULTS: Synergistic effects were observed in five cell lines from the combination of etoposide and rapamycin. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with up-regulation of phosphorylated c-Jun and down-regulation of Bcl-xL. The synergistic interaction of rapamycin and etoposide was lower when the c-Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in the model mice with ovarian cancer xenografts.CONCLUSIONS: Chemotherapy with rapamycin and etoposide combined is worth exploring as a treatment modality for women with epithelial ovarian cancer. |
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Authors:
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Hiroaki Itamochi; Tetsuro Oishi; Muneaki Shimada; Shinya Sato; Kazunori Uegaki; Jun Naniwa; Seiya Sato; Michiko Nonaka; Naoki Terakawa; Junzo Kigawa; Tasuku Harada |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-24 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: - ISSN: 1078-0432 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Dept. Obstetrics and Gynecology, Tottori University. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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