Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
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Kanako Inaba1, Katsutoshi Oda1, Kazuhiro Aoki2, Kenbun Sone1, Yuji Ikeda1, Aki Miyasaka1, Tomoko Kashiyama1, Tomohiko Fukuda1, Chinami Makii1, Takahide Arimoto1, Osamu Wada-Hiraike1, Kei Kawana1, Tetsu Yano3, Yutaka Osuga1, Tomoyuki Fujii1
1Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
2Imaging Platform for Spatio-Temporal Information, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan
Katsutoshi Oda, email: [email protected]
Keywords: ovarian mucinous carcinoma, MAPK pathway, PI3K/mTOR pathway, molecular target therapy, FRET imaging
Received: November 15, 2015 Accepted: March 29, 2016 Published: April 18, 2016
The aim of this study was to clarify the synergistic effects of dual inhibition of the PI3K/mTOR and MAPK pathways in ovarian mucinous carcinoma (OMC) cells, using fluorescence resonance energy transfer (FRET) imaging. We exposed 6 OMC cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib), and evaluated synergistic effects using the Chou–Talalay method. Then, S6K (PI3K pathway) and ERK (MAPK pathway) kinase activities, and their individual proliferative or cytotoxic effects were calculated by time-lapse FRET imaging. In combination with SAR245409, pimasertib (30 nM) synergistically inhibited cell growth (combination indexes: 0.03–0.5) and induced apoptosis in all 6 OMC cell lines. FRET-imaging results demonstrated that ERK inhibition induced both anti-proliferation and apoptosis in a dose-dependent manner in both MCAS and OAW42 cells. However, S6K inhibition suppressed proliferation in a threshold manner in both cell lines, although apoptosis was only induced in OAW42 cells. These results demonstrated that combined PI3K/mTOR and MEK inhibition exhibited synergistic antitumor effects in OMC cells and that FRET imaging is useful for analyzing kinase activities in live cells and elucidating their cytostatic and cytotoxic effects.
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