Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through upregulation of c-Jun.

Abstract

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.

• Authors: Hiroaki Itamochi, Tetsuro Oishi, Muneaki Shimada, Shinya Sato, Kazunori Uegaki, Jun Naniwa, Seiya Sato, Michiko Nonaka, Naoki Terakawa, Junzo Kigawa, Tasuku Harada
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 14 Pg. 4742-50 (Jul 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21610153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins c-jun
• Etoposide
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adenocarcinoma (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Etoposide (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Nude
• Ovarian Neoplasms (genetics, metabolism, mortality)
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Sirolimus (pharmacology)
• Survival Analysis
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays