RRC ID 63515
Author Inaba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T.
Title Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.
Journal Oncotarget
Abstract 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.
Volume 7(20)
Pages 29577-91
Published 2016-5-17
DOI 10.18632/oncotarget.8807
PII 8807
PMID 27102436
PMC PMC5045418
MeSH 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* Phosphoinositide-3 Kinase Inhibitors Quinoxalines / pharmacology Sulfonamides / pharmacology TOR Serine-Threonine Kinases / antagonists & inhibitors
IF 5.168
Human and Animal Cells JHOM-1(RCB1676) JHOM-2B(RCB1682) OMC-3(RCB0755)