Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through upregulation of c-Jun
| Autor: | Muneaki Shimada, Jun Naniwa, Tetsuro Oishi, Tasuku Harada, Shinya Sato, Junzo Kigawa, Naoki Terakawa, Hiroaki Itamochi, Michiko Nonaka, Kazunori Uegaki, Seiya Sato |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Cell Survival Proto-Oncogene Proteins c-jun medicine.medical_treatment Mice Nude Antineoplastic Agents Apoptosis Biology Pharmacology Adenocarcinoma chemistry.chemical_compound Mice Nude mouse Cell Line Tumor medicine Animals Humans Etoposide PI3K/AKT/mTOR pathway Cisplatin Ovarian Neoplasms Sirolimus Chemotherapy TOR Serine-Threonine Kinases Cancer medicine.disease biology.organism_classification Survival Analysis Xenograft Model Antitumor Assays Up-Regulation Gene Expression Regulation Neoplastic Oncology Paclitaxel chemistry Cancer research Female Ovarian cancer medicine.drug Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(14) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: The 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. This 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, and 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 upregulation of phosphorylated c-Jun and downregulation 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. Clin Cancer Res; 17(14); 4742–50. ©2011 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|