Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging

• Published in: Oncotarget Vol. 7; no. 20; pp. 29577 - 29591
• Main Authors: Inaba, Kanako, Oda, Katsutoshi, Aoki, Kazuhiro, Sone, Kenbun, Ikeda, Yuji, Miyasaka, Aki, Kashiyama, Tomoko, Fukuda, Tomohiko, Makii, Chinami, Arimoto, Takahide, Wada-Hiraike, Osamu, Kawana, Kei, Yano, Tetsu, Osuga, Yutaka, Fujii, Tomoyuki
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 17.05.2016
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Cell Line, Tumor; Cystadenocarcinoma, Mucinous; Drug Screening Assays, Antitumor - methods; Drug Synergism; Female; Fluorescence Resonance Energy Transfer - methods; Humans; MAP Kinase Kinase Kinases - antagonists & inhibitors; Models, Theoretical; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Quinoxalines - pharmacology; Research Paper; Sulfonamides - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; MAPK pathway; molecular target therapy; PI3K/mTOR pathway; FRET imaging; ovarian mucinous carcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8807

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.