Effect of simultaneous inhibition of MEK and PI3K/Akt pathways on paclitaxel sensitivity in ovarian cancer

Abstract

16046 Background: Paclitaxel (PTX) is one of the key drugs for ovarian cancer treatment. PTX activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3’-kinase (PI3K) pathways that lead to cell survival pathways. The purpose of this study was to clarify whether and how the inhibitors of MEK and/or PI3K affect the sensitivity to PTX in ovarian cancer cells. Methods: We treated five ovarian cancer cell lines in combination with PTX and MEK- [PD98059 (PD)] and/or PI3K-inhibitor [LY294002 (LY)] and assessed cell viability, apoptosis, and the expression of phosphorylated (p) MEK and pAkt. The sensitivity of the cell lines to PTX was determined by 3-(4,5- dimethylthiazol-2-yl) -2,5-dyphenyltetrazolium bromide (MTT) assay. The level of protein expression was analyzed by western blot analysis. The drug-induced apoptosis was assessed by Annexin V-FITC staining. Additionally, KOC-2S was injected to intraperitoneal cavity of nude mouse. The effect of combined treatment on the survival in xenograft model was investigated. Results: The levels of pMEK and pAkt protein expression were higher in PTX resistant cell lines (KOC-2S and KFTx) than that in sensitive cell lines (KF, SHIN-3, SK-OV-3). Treatment of PTX induced MEK activation in all five ovarian cancer cell lines. The combination of PTX with either PD or LY led to additive effect on cell growth inhibition. In contrast, synergistic effect was observed in the combination of PTX with PD and LY. Furthermore, apoptotic cells were significantly increased after exposure to PTX and both inhibitors in comparison with other treatment conditions, such as PTX alone, PTX with either PD or LY. The level of pMEK induced by PTX was down-regulated by PD. Interestingly, the level of pAkt was up-regulated by the combination of PTX with PD, which was reduced by LY. Treatment with PTX, PD, and LY prolonged survival in an ovarian cancer xenograft model (p < 0.01). Conclusions: The present study suggests that simultaneous inhibition of MEK and PI3K/Akt pathways enhances the sensitivity to PTX in ovarian cancer. The combination of PTX with MEK- and PI3K-inhibitor may be a new treatment strategy for ovarian cancer. No significant financial relationships to disclose.