Abstract 2561: Inhibiting the mTOR pathway synergistically enhances etoposide-induced cytotoxicity by upregulating c-Jun in ovarian cancer cells

Abstract Objective: The mammalian target of rapamycin (mTOR) pathway is considered 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. Rapamycin has been reported to enhance the effectiveness of several chemotherapeutic agents. The present study aimed to assess the potential of combination effects of rapamycin and anticancer drugs used as first- or second-line chemotherapy to treat ovarian cancer. Methods: Six cell lines of ovarian serous adenocarcinoma (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, TU-OS-4) were used in this study. We treated the cells with rapamycin combined with anticancer agents, then assessed cell viability, apoptosis, and the expression of proteins in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of combined treatment on survival in xenograft models with nude mice. Results: The protein expression levels of PTEN, phosphorylated (p) Akt, pmTOR, p4E-BP1, and pS6K1 were confirmed in all cell lines. Synergistic effects with rapamycin were observed in combination with etoposide in five cell lines, with doxorubicin in four lines, and with SN38, which is an active metabolite of camptothecin-11, in two lines. 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 model mice with ovarian cancer xenografts (P<0.001). Conclusion: Combination chemotherapy consisting of rapamycin and etoposide showed synergistic effect against epithelial ovarian cancer. This treatment modality is worth exploring further for patients with ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2561. doi:10.1158/1538-7445.AM2011-2561